Resorcinol compounds for dermatological use

ABSTRACT

Provided herein are methods and compositions comprising resorcinol derivatives for the use of treating, regulating or preventing a skin condition characterized by oxidative stress or a degenerative process. Methods of preventing, lightening or reducing the appearance of visible discontinuities of the skin resulting from skin pigmentation, skin aging, or other disorders are also disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application claims priority benefit of U.S. ProvisionalPatent Application No. 61/775,384, filed Mar. 8, 2013. The entirecontents of that application are hereby incorporated by referenceherein.

TECHNICAL FIELD

Provided herein are cosmetic and dermatological compositions, such asresorcinol derivatives, with anti-aging, skin even-toning, and otheruseful properties for skin treatment.

BACKGROUND

Natural-looking skin is influenced by a number of physiological andgenetic factors. Standard definitions of beautiful skin include skinhaving a transparent quality with uniform undertones of color and novisible or tactile discontinuities. The basis for this natural-lookingappearance is in the skin structure itself. The outer layer of humanskin is a semi-transparent layer known as the stratum corneum. Thetransparency of the stratum corneum permits glimpses of the deeperlayers of skin, where blood vessels and pigments reside. The palereddish hue of the blood vessels' hemoglobin, and the brown/black hue ofmelanin that is the primary skin pigment, combine to produce the skin'scolor. Ideal skin should also be smooth and even, with no apparentsurface flaws in addition to having the transparent look with uniformcolor distribution.

Skin is composed of a top layer, the epidermis, which is approximately20 cell layers or about 0.1 mm in thickness, and a lower layer, thedermis, which is from about 1 to about 4 mm in thickness and containssmall blood vessels, collagen, elastin and fibroblasts. The dermisprovides structural support and nutrients to the epidermis. Aging hasbeen shown to increase cellular heterogeneity of the epidermal layer.Aging does not affect the number of cell layers in the epidermis, butthe overall thickness decreases. The supporting dermis is known to thinwith age and exposure to the sun and environmental contaminants. Thedermal layer provides the support and blood supply for the epidermis,therefore the dermal layer is important in maintaining the elasticityand appearance of the skin.

Considerable effort has been expended to find ways to prevent adversechanges in the skin brought about by ultraviolet (UV) exposure and othercauses. Preventative approaches include physically blocking or absorbingthe UV radiation before it can enter the skin using UV absorbingcompounds. Skin problems in aging individuals can result from a varietyof extrinsic or intrinsic factors such as harmful UV radiation from thesun, exposure to the environment, stress, fatigue, disease, or acombination thereof.

Many people at different stages of their life are concerned with thedegree of pigmentation of their skin and may wish to reduce the skindarkening, or may wish to lighten or even-tone their natural skin color.The mechanism by which skin pigmentation is formed, melanogenesis, isparticularly complex and schematically involves the following mainsteps: Tyrosine→L-Dopa→Dopaquinone→Dopachrome→Melanins. The first tworeactions in this series are catalyzed by the enzyme tyrosinase. Theactivity of tyrosinase is promoted by the action of α-melanocytestimulating hormone or UV rays. It is well established that a substancehas a depigmenting effect if it acts directly on the vitality of theepidermal melanocytes where melanogenesis normally occurs and/or if itinterferes with one of the stages in melanin biosynthesis. Pigmentationdisorders can take a variety of forms like hyperpigmentation,hypopigmentation, and uneven pigmentation, and include but are notlimited to melasma (mask of pregnancy or chloasma), liver spots (whichoften develop with age) and leukoderma such as vitiligo. Some of thepigmentation occurs as a side effect of birth control pills, as a resultof skin damage such as a persistent result of acne, burns, bites andother skin injuries, as after-burn scars, as cicatrical spots, asstretch mark scars, and as dark circles and puffiness under and aroundthe eyes. The degree of pigmentation disorders of the skin in many casesincreases with the age of the individuals. Because of the involvement oftyrosinase in melanogensis, tyrosinase inhibition assays are often usedto screen potential skin lightening agents. Some mushroom tyrosinases(such as that from Agaricus bisporus) are homologous with mammaliantyrosinase, and mushroom tyrosinase is often used in inhibition assaysdue to its ready commercial availability. However, the enzyme inhibitionassays may not be as good an indicator of activity as assays which aremore similar to the intended clinical or cosmetic use, such as theMatTek Corporation's MelanoDerm™ Skin Model (a system which consists ofnormal, human-derived epidermal keratinocytes and melanocytes formedinto a multilayered model of human epidermis).

In the United States, the most commonly used treatment forhyperpigmentation is 1,4-benzenediol, which is known as hydroquinone.Treatment with hydroquinone interferes with the action of tyrosinase,which is an enzyme used in the synthesis of melanin, and compositionsare sold across the counter at about 2% hydroquinone and by prescriptionat higher concentrations. Hydroquinone compositions are effective buthave some undesirable side effects. These can be burning, redness,sensitization and irritation in some patients. U.S. Pat. No. 4,526,179refers to certain hydroquinone fatty esters that have good activity andare less irritating and more stable than hydroquinone. Japanese PatentApplication No. 27909/86 (JP 61-27909) refers to other hydroquinonederivatives that do not have the drawbacks of hydroquinone but that haverelatively poor efficacy. Other compounds with a hydroquinone corestructure have been described in the patent literature, for example,U.S. Pat. No. 5,449,518 refers to 2,5-dihydroxyphenyl carboxylic acidderivatives, and European Patent Application EP 341,664A1 and PCTInternational Publication WO 99/15148 refer to certain resorcinolderivatives as tyrosinase inhibitors.

A variety of additional agents have been applied to the skin to lightenthe skin. Such agents include but are not limited to kojic acid,licorice and its derivatives, ascorbic acid and its derivatives,arbutin, bearberry, Glycyrrhiza glabra and its derivatives, Chlorellavulgaris extract, perilla extract, and coconut fruit extract. Perillaextract is disclosed as a whitening agent in U.S. Pat. No. 5,980,904 andJapanese Publications Nos. 07-025742, 07-187989, 10-265322, 2001-163759and 2001-181173. Coconut fruit extract is disclosed as a whitening agentin Japanese Patent No. 2896815 B2.

Resorcinol (1,3-benzenediol) derivatives have been used to providecosmetic benefits to skin and hair. 4-Substituted resorcinol derivativeshave been used for skin lightening; see, for example, U.S. Pat. No.4,959,393, U.S. Pat. No. 6,132,740, U.S. Pat. No. 6,504,037, U.S. PatentApplication Publication No. 2008/0131382, and Japanese Published PatentApplication Nos. JP 2001-01 0925 and JP 2000-327557. Resorcinolderivative dimers which are inhibitors of tyrosinase are disclosed inU.S. Pat. No. 5,399,785. Resorcinol-type skin lightening agents, whichcan be synthesized using coumarin as starting material, are disclosed inU.S. Patent Application Publication No. 2004/0042983. However, some ofthese compounds can be difficult to formulate, or may cause skinirritation.

It would be desirable to have a safe and non-toxic composition for thetreatment or prevention of the pigmentation disorders. The compounds andcompositions comprising resorcinols described herein fill this need.

BRIEF DESCRIPTION

Provided herein are methods for reducing or improving the appearance ofvisible discontinuities in skin associated with age-related damage, ordamage resulting from harmful ultraviolet radiation, such as thatcontained in sunlight, pollution and other environmental insults,stress, or fatigue. Also provided herein are methods for reducing theappearance of coloration due to pigmentation disorders. Also providedare compositions and methods of improving skin appearance by alleviatingskin discoloration associated with age and reducing the appearance ofcoloration due to pigmentation disorders simultaneously. Also providedare resorcinol derivatives for reducing or preventing the appearance ofskin pigmentation and the skin problems arising with age, andcompositions comprising such resorcinol derivatives, suchpharmaceutically acceptable compositions, including topicalpharmaceutically acceptable compositions.

Also provided are methods for reducing or improving the appearance ofpigmentation or discoloration in skin. Also provided are methods ofreducing age spots, liver spots, and other age-related pigmentationdisorders, and method of treating pigmentation disorders such asvitiligo and melasma. The methods comprise applying a therapeutically orcosmetically effective amount of the compounds to the skin in an amountsufficient to reduce or improve the appearance of pigmentation ordiscoloration in skin, or in an amount sufficient to reduce age spots,liver spots, or other age-related pigmentation disorders, or in anamount sufficient to treat a pigmentation disorder, such as vitiligo andmelasma. Also provided are compounds for use in reducing or improvingthe appearance of pigmentation or discoloration in skin, or for use inreducing age spots, liver spots, or other age-related pigmentationdisorders, or for use in treating a pigmentation disorder, such asvitiligo and melasma.

The resorcinol derivatives provided herein, which are defined below andused in the various methods provided herein, are useful in the treatmentor prevention of one or more dermatological conditions as desired by thesubject being treated, such as for medicinal or cosmetic purposes, suchas to prevent, lighten, reduce or treat the signs or appearance ofundesired pigmentation of skin affected by the one or more conditions.

Provided herein is a cosmetic or dermatological composition comprisingone or more resorcinols of formula I:

wherein R¹ and R² are independently alkyl, alkenyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, or halo, each of which alkyl,alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionallysubstituted with —OH, —OR³, —NR³R⁴, —C(O)OR³, —C(O)NR³R⁴, or halo; andR³ and R⁴ are independently hydrogen, alkyl, alkenyl, cycloalkyl,heterocycloalkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, arylalkyl,heteroarylalkyl, aryl, or heteroaryl; or a pharmaceutically acceptablesalt thereof. Also provided are mixtures of two or more compounds offormula I. In some variations, R¹ is alkyl or halo, and R² is alkyl orcycloalkyl. In some variations, R¹ is alkyl, such as methyl. In somevariations, R¹ is haloalkyl, perhaloalkyl, fluoroalkyl, orperfluoroalkyl, such as trifluoromethyl. In some variations, R¹ is halo,such as fluoro, chloro, bromo, or iodo. In some variations, R¹ is fluoroor chloro. In some variations, R² is alkyl, such as ethyl or hexyl. Insome variations, R² is cycloalkyl, such as cyclohexyl.

In some variations, R¹ is (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,(C₃-C₈)-cycloalkyl, (C₃-C₈)-heterocycloalkyl, (C₆-C₁₂)-aryl,(C₃-C₁₂)-heteroaryl, or halo, each of which (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl, (C₃-C₈)-heterocycloalkyl,(C₆-C₁₂)-aryl, or (C₃-C₁₂)-heteroaryl is optionally substituted withone, two, or three substituents selected from the group consisting of—OH, —OR³, —NR³R⁴, —C(O)OR³, —C(O)NR³R⁴, or halo; and R² is(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl,(C₃-C₈)-heterocycloalkyl, (C₆-C₁₂)-aryl, (C₃-C₁₂)-heteroaryl, or halo,each of which (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl,(C₃-C₈)-heterocycloalkyl, (C₆-C₁₂)-aryl, or (C₃-C₁₂)-heteroaryl isoptionally substituted with one, two, or three substituents selectedfrom the group consisting of —OH, —OR³, —NR³R⁴, —C(O)OR³, —C(O)NR³R⁴, orhalo.

In some variations, R¹ is (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,(C₃-C₈)-cycloalkyl, (C₃-C₈)-heterocycloalkyl, (C₆-C₁₂)-aryl,(C₃-C₁₂)-heteroaryl, or halo, each of which (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl, (C₃-C₈)-heterocycloalkyl,(C₆-C₁₂)-aryl, or (C₃-C₁₂)-heteroaryl is optionally substituted withone, two, or three substituents selected from the group consisting of—OH, —OR³, —NR³R⁴, —C(O)OR³, —C(O)NR³R⁴, or halo; and R² is cycloalkyl,such as (C₃-C₈)-cycloalkyl, such as cyclohexyl.

In some variations, R³ and R⁴ are independently hydrogen, (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl, (C₃-C₈)-heterocycloalkyl,(C₃-C₈)-cycloalkyl-(C₁-C₆)-alkyl,(C₃-C₈)-heterocycloalkyl-(C₁-C₆)-alkyl, (C₆-C₁₂)-aryl-(C₁-C₆)-alkyl,(C₃-C₁₂)-heteroaryl-(C₁-C₆)-alkyl, (C₆-C₁₂)-aryl, or(C₃-C₁₂)-heteroaryl.

In some variations, R¹ is (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,(C₃-C₈)-cycloalkyl, or halo, and R² is (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,or (C₃-C₈)-cycloalkyl.

In some variations, R¹ is (C₁-C₆)-alkyl or halo, and R² is (C₁-C₆)-alkylor (C₃-C₈)-cycloalkyl.

In some variations, R¹ is methyl, fluoro, or trifluoromethyl, and R² isethyl, hexyl, or cyclohexyl.

In particular variations, the cosmetic or dermatological compositioncontains one or more of the following compounds:

or a pharmaceutically acceptable salt thereof.

In some variations, the cosmetic and dermatological compositionscomprising one or more compounds of formula I may be used for theprophylaxis and treatment of cosmetic and dermatological skin changes ina subject in need thereof, such as undesirable skin pigmentation orchanges in skin pigmentation or skin tone, which is achieved byadministering an effective amount of one or more of the compositions tothe subject. In some variations, the skin changes are produced byoxidative or degenerative processes.

In some variations, the cosmetic and dermatological compositionscomprising one or more compounds of formula I may be used forpreventing, lightening or reducing visible signs from aging in asubject, which is achieved by administering an effective amount of oneor more of the compositions to the subject. In some variations, thecosmetic and dermatological compositions comprising one or morecompounds of formula I may be used in a subject for reducing theappearance of visible, tactile, and/or coloration discontinuities inskin associated with aging, age-related damage, or damage resulting fromharmful factors, such as those contained in sunlight, harmfulultraviolet radiation, pollution and other environmental insults,stress, or fatigue, which is achieved by administering an effectiveamount of one or more of the compositions to the subject.

In some variations, the cosmetic and dermatological compositionscomprising one or more compounds of formula I may be used in a subjectfor the prophylaxis or treatment of dermatological conditions comprisingunevenness or pigmentation of the skin, which is achieved byadministering an effective amount of one or more of the compositions tothe subject.

In some variations, the cosmetic and dermatological compositionscomprising one or more compounds of formula I may be used in a subjectfor preventing, lightening or reducing the appearance of visible and/ortactile discontinuities of the skin, such as mottling, which is achievedby administering an effective amount of one or more of the compositionsto the subject.

In some variations, the cosmetic and dermatological compositionscomprising one or more compounds of formula I may be used in a subjectfor preventing, lightening or reducing the appearance of visiblediscontinuities of the skin resulting from the aging processes, which isachieved by administering an effective amount of one or more of thecompositions to the subject.

In some variations, the cosmetic and dermatological compositionscomprising one or more compounds of formula I may be used in a subjectfor preventing, lightening or reducing the appearance of visiblediscontinuities of the skin such as pigmentation, age spots, vitiligoand melasma, which is achieved by administering an effective amount ofone or more of the compositions to the subject.

In some variations, the cosmetic and dermatological compositionscomprising one or more compounds of formula I may be used in a subjectfor preventing, lightening or reducing the appearance of visiblediscontinuities of the skin such as coloration, discoloration, orpigmentation resulting from stress, fatigue, or extrinsic insults suchas harmful factors contained in sunlight, harmful ultraviolet radiation,pollution and other environmental insults, which is achieved byadministering an effective amount of one or more of the compositions tothe subject.

In some variations, the cosmetic and dermatological compositionscomprising one or more compounds of formula I may be used forpreventing, lightening or reducing the appearance of dark circles, darkspots and uneven skin tone, which is achieved by administering aneffective amount of one or more of the compositions to the subject.

In another variation, the cosmetic and dermatological compositionscomprising one or more compounds of formula I may be used for reducingthe appearance of visible discontinuities in skin associated withinflammation, which is achieved by administering an effective amount ofone or more of the compositions to the subject. The visiblediscontinuities may be caused by post-inflammatory hypopigmentation orhyperpigmentation. The inflammation may be due to various causes. Theinflammation may be caused by rosacea. The inflammation may be caused bydiaper rash. The inflammation may be caused by acne. The inflammationmay be caused by dermatitis such as atopic dermatitis, contactdermatitis, or seborrheic dermatitis. The inflammation may be caused bypoison ivy or poison oak. The inflammation may be caused by erythema.The inflammation may be caused by psoriasis.

Also provided herein is a cosmetic composition comprising a cosmeticallyacceptable or dermatologically acceptable carrier in combination withany one or more of the compounds of formula I. The carrier can beformulated for topical use.

Also provided herein is a cosmetic composition comprising apharmaceutically acceptable carrier in combination with any one or moreof the compounds of formula I.

In one variation, provided herein are methods for reducing theappearance of visible discontinuities in skin, such as coloration,discoloration, or pigmentation discontinuities, with a compositioncomprising one or more compounds of formula I, wherein the compositionis included in a topical formulation, comprising administering aneffective amount of the composition to a subject.

In one variation, provided herein are methods for reducing theappearance of visible discontinuities in skin such as coloration,discoloration, or pigmentation discontinuities, with a compositioncomprising one or more compounds of formula I, wherein the compositionis included in a topical pharmaceutical formulation, comprisingadministering an effective amount of the one or more compounds offormula I to a subject. In further embodiments, the administration istopical or dermatological administration. The composition can comprisepharmaceutically and/or dermatologically acceptable carriers andvehicles.

In one variation, provided herein are methods for reducing theappearance of visible discontinuities in skin such as coloration,discoloration, or pigmentation discontinuities, with a compositioncomprising one or more compounds of formula I, wherein the compositionis formulated for transdermal administration, comprising administeringan effective amount of the one or more compounds of formula I to theskin of a subject. The composition can comprise pharmaceutically and/ordermatologically acceptable carriers and vehicles.

Also provided herein is a method of lightening skin of a subject whileproviding reduction or treatment or prevention of signs of skin aging,comprising administering to said subject an amount of one or morecompounds of formula I effective for even-toning, skin-lightening orpigmentation-reducing. In further embodiments, the administration istopical or dermatological administration. In a particular variation,provided herein is a method of lightening skin of a subject in need ofsaid treatment while providing reduction or treatment or prevention ofsigns of skin aging, comprising administering to said subject an amountof a composition comprising a compound of formula I effective toeven-tone the skin, lighten the skin, or reduce pigmentation in theskin. In further embodiments, the administration is topical ordermatological administration. The composition can comprisepharmaceutically and/or dermatologically acceptable carriers andvehicles.

Further provided is a method of improving the appearance of skin of asubject, comprising administering to said subject an amount of acomposition comprising a compound of formula I effective to reducepigmentation. In further embodiments, the administration is topical ordermatological administration. In a particular variation, providedherein is a method of reducing or preventing the appearance ofpigmentation in a subject in need of said treatment, comprisingadministering to said subject an amount of a composition comprising acompound of formula I effective to reduce the appearance of pigmentationin a subject or to prevent the appearance of pigmentation in a subject.The composition can comprise pharmaceutically and/or dermatologicallyacceptable carriers and vehicles. In some variations, provided is amethod of treating pigmentation or reducing the appearance ofpigmentation or prophylaxis against the appearance of pigmentation, byadministering an effective amount of a composition comprising a compoundof formula I. In some variations the subject has a pigmentation disorderselected from age spots, vitiligo and melasma.

In another variation, provided herein is a method of treating orregulating a skin condition characterized by oxidative stress comprisingadministering to a subject exhibiting said skin condition a compositioncomprising one or more compounds of formula I. The composition cancomprise pharmaceutically and/or dermatologically acceptable carriersand vehicles. In further embodiments, the administration is topical ordermatological administration.

In another variation, provided herein is a method of regulating and/orpreventing visible signs of skin aging comprising administering to asubject exhibiting skin damage due to aging, a composition comprisingone or more compounds of formula I. The composition can comprisepharmaceutically and/or dermatologically acceptable carriers andvehicles. In further embodiments, the administration is topical ordermatological administration.

In another variation, provided herein is a method of regulating and/orpreventing visible signs of skin damage due to extrinsic factorscomprising administering to a subject exhibiting skin damage acomposition comprising an effective amount of one or more compounds offormula I. The composition can comprise pharmaceutically and/ordermatologically acceptable carriers and vehicles. In furtherembodiments, the administration is topical or dermatologicaladministration. The extrinsic factors can include, but are not limitedto, diaper rash, erythema, UV radiation damage, sunburn, photoaging,contact dermatitis, and combinations thereof.

Also provided herein is a method of reducing the appearance ofpigmentation and aging processes in the skin of a subject, comprisingadministering to said subject an amount of a composition comprising oneor more compounds of formula I effective to reduce the appearance ofpigmentation, or to prevent the appearance of pigmentation, incombination with another therapeutic agent. In one variation, providedherein is a method of reducing the appearance of pigmentation, orpreventing the appearance of pigmentation, in the skin of a subject,comprising administering to said subject an effective amount of acomposition comprising one or more compounds of formula I in combinationwith an antioxidant. In one variation, provided herein is a method ofreducing the appearance of pigmentation and aging processes, orpreventing the appearance of pigmentation and aging processes, in asubject in need of said treatment, comprising administering to saidsubject an effective amount of a composition comprising one or morecompounds of formula I in combination with ascorbic acid or derivativesthereof. In another variation, provided herein is a method of reducingthe appearance of pigmentation and aging processes, or preventing theappearance of pigmentation and aging processes, in a subject in need ofsaid treatment, comprising administering to said subject an effectiveamount of a composition comprising one or more compounds of formula I incombination with alpha-tocopherol or any mixture of tocopherols orderivatives thereof. In another variation, provided herein is a methodof reducing the appearance of pigmentation and aging processes, orpreventing the appearance of pigmentation and aging processes, in asubject in need of said treatment, comprising administering to saidsubject an effective amount of a composition comprising one or morecompounds of formula I in combination with alpha-tocotrienol or anymixture of tocotrienols or derivatives thereof. In another variation,provided herein is a method of reducing the appearance of pigmentationand aging processes, or preventing the appearance of pigmentation andaging processes, in a subject in need of said treatment, comprisingadministering to said subject an effective amount of a compositioncomprising one or more compounds of formula I in combination with anymixture of tocopherols and tocotrienols or derivatives thereof. In yetanother variation, provided herein is a method of reducing theappearance of pigmentation and aging processes, or preventing theappearance of pigmentation and aging processes, in a subject in need ofsaid treatment, comprising administering to said subject an effectiveamount of a composition comprising one or more compounds of formula I incombination with ascorbic acid and alpha-tocopherol or derivativesthereof. In other variations, provided herein is a method of reducingthe appearance of pigmentation and aging processes, or preventing theappearance of pigmentation and aging processes, in a subject in need ofsaid treatment, comprising administering to said subject an effectiveamount of a composition comprising one or more compounds of formula I incombination with retinoids or an exfoliating agent. When administered incombination, the therapeutic agents can be formulated as separatecompositions that are given at the same time or different times, or thetherapeutic agents can be given as a single composition. The compositioncan also comprise pharmaceutically and/or dermatologically acceptablecarriers and vehicles. In any of the foregoing embodiments, theadministration can be topical or dermatological administration.

Also provided herein is a product comprising instructions directing auser to apply a composition including a skin care composition comprisingone or more compounds of formula I. The composition can comprisepharmaceutically and/or dermatologically acceptable carriers andvehicles.

Also provided herein is a kit, comprising a container comprising one ormore specific compounds or dermatological compositions described hereinthat lighten skin pigmentation. The kit may further comprise printedinstructions as a label or a package insert directing the use of theenclosed compound or composition to lighten skin pigmentation.

Also provided for herein is the use of a composition of any of theforegoing variations in the manufacture of a cosmetic or dermatologicalcomposition for treating a mammalian subject, such as a human, having adermatologic condition, where the treatment is to prevent, reduce ortreat signs of skin aging or skin pigmentation, or to reduce theappearance of skin aging or skin pigmentation.

For all compositions described herein, and all methods using acomposition described herein, the compositions can either comprise thelisted components or steps, or can “consist essentially of” the listedcomponents or steps. When a composition is described as “consistingessentially of” the listed components, the composition contains thecomponents listed, and may contain other components which do notsubstantially affect the skin or the skin condition being treated, butdo not contain any other components which substantially affect the skinor the skin condition being treated other than those componentsexpressly listed; or, if the composition does contain extra componentsother than those listed which substantially affect the skin or the skincondition being treated, the composition does not contain a sufficientconcentration or amount of the extra components to substantially affectthe skin or the skin condition being treated. When a method is describedas “consisting essentially of” the listed steps, the method contains thesteps listed, and may contain other steps that do not substantiallyaffect the skin or the skin condition being treated, but the method doesnot contain any other steps which substantially affect the skin or theskin condition being treated other than those steps expressly listed.

DETAILED DESCRIPTION Definitions

As used herein, a “subject” or “patient” is a mammal, particularly ahuman. It is understood that use “in” a subject or patient can compriseuse “on” a subject or patient as well; that is, use “in” a subject orpatient can comprise either internal use, external use, or both,according to the context of the use.

As used herein, the terms “even-toning”, “whitening”, “lightening” and“depigmentation” agent are used interchangeably throughout thisdocument. For purposes of skin lightening, topical application of skinlightening agent should have a lightening effect on only the area to betreated, preferably produce no or minimal irritation, preferably produceno or minimal post-inflammatory secondary pigmentation, and preferablynot cause an allergic reaction. In addition, the skin lightening shouldbe effective for normal cutaneous pigmentation and its excesses,including, but not limited to, lentigo senilis, chloasma, cicatricalbrown spots, and hyperpigmentation after use of photosensitizingproducts. Preferably, the skin lightening should be effective whilesimultaneously providing anti-aging skin benefits.

As used herein, a “skin-lightening or pigmentation reducing amount of acompound of formula I” means an amount or concentration of the compoundcapable of detectably lightening skin or reducing pigmentation in asubject, such as a human, as determined by any standard assay. Theactive compound is typically administered in a dermatological orpharmaceutical composition for a standard course of treatment thatproduces the desired result of skin depigmentation.

As used herein, “administering to skin in need of such treatment” meanscontacting (e.g., by use of the hands or an applicator such as, but notlimited to, a wipe, tube, roller, spray, or patch) the area of skin inneed such treatment or an area of skin proximate to the area of skin inneed of such treatment.

As used herein, “composition” means a composition suitable for topicaladministration to the skin.

As used herein, the term “cosmetics” includes make-up, foundation, andskin care products. The term “make-up” refers to products that leavecolor on the face, including foundations, blacks and browns, e.g.,mascara, concealers, eye liners, brow colors, eye shadows, blushers, lipcolors, and so forth. The term “foundation” refers to liquid, creme,mousse, pancake, compact, concealer, or like products that even out theoverall coloring of the skin. Foundation is typically manufactured towork better over moisturized and/or oiled skin. The term “skin careproducts” refers to products used to treat or otherwise care for,moisturize, improve, or clean the skin. Products contemplated by thephrase “skin care products” include, but are not limited to, adhesives,bandages, anhydrous occlusive moisturizers, antiperspirants, facial washcleaners, cold cream, deodorants, soaps, occlusive drug deliverypatches, powders, tissues, wipes, solid emulsion compact, anhydrous hairconditioners, medicated shampoos, scalp treatments and the like.

As used herein, the term “cosmetically-acceptable” or“dermatologically-acceptable” means that the compositions or componentsthereof so-described are suitable for use in contact with skin,particularly human skin, without undue toxicity, incompatibility,instability, irritation, or allergic response.

As used herein, the term “cosmetically acceptable carrier”,“cosmetically acceptable excipient”, “dermatologically acceptablecarrier” or “dermatologically acceptable excipient” includes any and allsolvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents and the like, that arecosmetically acceptable or dermatologically acceptable. The use of suchmedia and agents for cosmetically active substances is well known in theart. Except insofar as any conventional media or agent is incompatiblewith the active ingredient, its use in the cosmetic compositions iscontemplated. Supplementary active ingredients can also be incorporatedinto the compositions. Dermatologically acceptable carriers are suitablefor topical application to the skin, have good aesthetic properties, arecompatible with the active agents described herein and any othercomponents, and cause minimal or no safety or toxicity concerns. A safeand effective amount of carrier is from about 50% to about 99.99% orabout 50% to about 99%, preferably from about 80% to about 99.9% orabout 75% to about 99%, more preferably from about 90% to about 98%, andmost preferably from about 90% to about 95% or about 85% to about 95% ofthe composition. The percentages are preferably percent by weight.

As used herein, the term “effective amount” refers to that amount of acompound described herein that is sufficient to effect treatment, asdefined below, when administered to a subject in need of such treatment.The effective amount will vary depending upon the subject and skincondition or disease condition being treated and the like, all of whichcan readily be determined by one of ordinary skill in the art.

As used herein, “regulating a skin condition” includes regulating theappearance of a skin condition, including visible discontinuities inskin such as, but not limited to, coloration, discoloration, andunwanted pigmentation. Regulating a skin condition includes even-toningthe skin and reducing pigmentation.

As used herein, “signs of skin aging” include, but are not limited to,all outward manifestations of skin aging which are visibly perceptibledue to changes in skin pigmentation, skin coloration, or skindiscoloration. Such signs may be induced or caused by intrinsic factorsor extrinsic factors, e.g., chronological aging and/or environmentaldamage (e.g., sunlight; UV; smoke, including cigarette, cigar or othertobacco product smoke; ozone; pollutants; stress; etc.). These signsinclude, but are not limited to, blotching (e.g., uneven red colorationdue to, e.g., rosacea), sallowness (pale color), discoloration caused bytelangiectasia or spider vessels; melanin-related hyperpigmented (orunevenly pigmented) skin regions such as age spots (liver spots, brownspots) and freckles; post-inflammatory hyperpigmentation orhypopigmentation such as that which occurs following an inflammatoryevent (e.g., as an acne lesion, in-grown hair, insect/spider bite orsting, scratch, cut, wound, abrasion, and the like); and tissueresponses to insult such as itch or pruritus.

As used herein, the terms “skin condition”, “dermatologic condition”,and “dermatological condition” are used interchangeably.

As used herein, the term “sunscreen” may include, but is not limited to,organic or inorganic sunscreens, such as methoxycinnamate, oxybenzone,avobenzone, and the like; sun blocks such as titanium oxide and zincoxide; and skin protectants; or mixtures thereof.

As used herein, the term “topical application” means to apply or spreadthe compositions described herein onto the surface of the skin.

As used herein, the terms “treat” and “treating”, and the like refer toreversing, alleviating, or inhibiting the progress of, the disorder orcondition to which such term applies, or one or more symptoms of suchdisorder or condition. The term “treatment”, as used herein, refers tothe act of treating, as “treating” is defined immediately above. Theterm “treatment” or “treating” includes the reduction in appearance ofskin imperfections irrelevant of the mechanism of action. One ofordinary skill in the art will appreciate that the endpoint of treatmentchosen in a particular case will vary according to the disease,condition, or disorder being treated, the outcome desired by thepatient, subject, or treating physician, and other factors. Where thecomposition is being used to lighten skin color such as, for example, toreverse hyperpigmentation caused by, for example, diseases such asmelasma or age spots, any one of a number of endpoints can be chosen.For example, endpoints can be defined subjectively such as, for example,when the subject is simply “satisfied” with the results of thetreatment. For pharmacological compositions, the endpoint can bedetermined by the patient's, subject's, or the treating physician's,satisfaction with the results of the treatment. Alternatively, endpointscan be defined objectively. For example, the patient's or subject's skinin the treated area can be compared to a color chart. Treatment isterminated when the color of the skin in the treated area is similar inappearance to a color on the chart. Alternatively, the reflectance ofthe treated skin can be measured, and treatment can be terminated whenthe treated skin attains a specified reflectance. Alternatively, themelanin content of the treated skin can be measured. Treatment can beterminated when the melanin content of the treated skin reaches aspecified value. Melanin content can be determined in any way known tothe art, including by histological methods, with or without enhancementby stains for melanin.

As used herein, “alkyl” is intended to embrace a saturated linear orbranched hydrocarbon chain having the number of carbon atoms specified.In one embodiment, alkyl groups can have 1 to 12 carbon atoms.“Alkylene” is intended to embrace a divalent saturated linear orbranched hydrocarbon chain having the number of carbon atoms specified.In one embodiment, alkylene groups can have 1 to 12 carbon atoms.

As used herein, “cycloalkyl” is intended to embrace a saturated cyclichydrocarbon chain having the number of carbon atoms specified. In oneembodiment, cycloalkyl groups can have 3 to 12 carbon atoms.

As used herein, “alkenyl” is intended to embrace a linear or branchedhydrocarbon chain having at least one carbon-carbon double bond. In oneembodiment, alkenyl groups can have 2 to 12 carbon atoms. “Alkenylene”is intended to embrace a divalent linear or branched hydrocarbon chainhaving at least one carbon-carbon double bond, and having the number ofcarbon atoms specified. In one embodiment, alkenylene groups can have 2to 12 carbon atoms.

As used herein, “haloalkyl” indicates an alkyl group where at least onehydrogen of the alkyl group has been replaced with a halogensubstituent, that is, a fluorine (F), chlorine (Cl), bromine (Br), oriodine (I) substituent. “Perhaloalkyl” indicates an alkyl group whereall available valences have been substituted with halogen. For example,“perhaloethyl” can refer to —CCl₂CF₃, —CF₂CBr₃, or —CCl₂CCl₃.

As used herein, “fluoroalkyl” indicates an alkyl group where at leastone hydrogen of the alkyl group has been replaced with a fluorinesubstituent. “Perfluoroalkyl” indicates an alkyl group where allavailable valences have been substituted with fluorine. For example,“perfluoroethyl” refers to —CF₂CF₃.

As used herein, “chloroalkyl” indicates an alkyl group where at leastone hydrogen of the alkyl group has been replaced with a chlorinesubstituent. “Perchloroalkyl” indicates an alkyl group where allavailable valences have been substituted with chlorine. For example,“perchloroethyl” refers to —CCl₂CCl₃.

As used herein, “aryl” is defined as an optionally substituted aromaticring system, such as phenyl or naphthyl. Aryl groups include monocyclicaromatic rings and polycyclic aromatic ring systems containing thenumber of carbon atoms specified. In one embodiment, aryl groups cancontain six to twenty carbon atoms. In other embodiments, aryl groupscan contain six to twelve carbon atoms, or six to ten carbon atoms. Inother embodiments, aryl groups can be unsubstituted. In otherembodiments, aryl groups can be substituted.

As used herein, “heterocycloalkyl” is intended to embrace an optionallysubstituted cyclic hydrocarbon chain having the number of carbon atomsspecified and one or more heteroatoms (such as one to three heteroatoms,such as oxygen, nitrogen, sulfur, and phosphorus). In one embodiment,heterocycloalkyl groups can have 3 to 12 carbon atoms and 1 to 3heteroatoms. Examples of heterocycloalkyl groups include, but are notlimited to, tetrahydrofuranyl, piperidinyl, and piperazinyl. In someembodiments, heterocycloalkyl groups can be unsubstituted. In otherembodiments, heterocycloalkyl groups can be substituted.

As used herein, “heteroaryl” is defined as an optionally substitutedaromatic ring system which contains the number of carbon atomsspecified, and one or more heteroatoms (such as one to threeheteroatoms), where heteroatoms include, but are not limited to, oxygen,nitrogen, sulfur, and phosphorus. In some embodiments, heteroaryl groupscan contain three to twelve carbon atoms and one to three heteroatoms,or six to ten carbon atoms and one to three heteroatoms. In someembodiments, heteroaryl groups can be unsubstituted. In otherembodiments, heteroaryl groups can be substituted. Examples ofheteroaryl groups include, but are not limited to, imidazolyl, pyrrolyl,and pyridinyl.

As used herein, the term “tocopherols or tocotrienols” encompasses afamily of molecules characterized by a 6-chromanol ring structure and aside chain at the 2-position. Tocopherols possess a4′,8′,12′-trimethyltridecyl phytol side chain, while tocotrienolspossess an unsaturated phytol side chain. As used herein, the termtocopherol or tocotrienols means alpha-, beta-, gamma- or delta-,epsilon- and zeta-tocopherol or tocotrienols (see The Merck Index(1996), Merck & Co., Whitehouse Station, N.J. 1620-1621 and 1712, andreferences cited therein), as well as Vitamin E. The term tocopherolalso includes cosmetically acceptable esters, for example tocopherolacetate, tocopherol lineate, or tocopherol stearate. The term tocopherolalso includes mixtures of tocopherols, tocotrienols and/or stereoisomersas well as enriched compositions comprising at least 50% of anytocopherol or tocotrienol. The tocopherols and tocotrienols can be ofnatural or synthetic origin.

As used herein, the term “retinoids” means retinol, retinal, esters ofretinol, retinyl palmitate, retinyl linoleate, retinoic acid, orretinoic acid esters, as well as synthetic or natural Vitamin A. Theterm “retinol” includes the following isomers of retinol:all-trans-retinol, 13-cis-retinol, 11-cis-retinol, 9-cis-retinol,3,4-didehydro-retinol. A retinyl ester is an ester of retinol. Suitableretinyl esters are C₁-C₃₀ esters of retinol, preferably C₂-C₂₀ esters,and most preferably C₂, C₃, and C₁₆ esters. Some esters may be selectedfrom retinyl palmitate, retinyl acetate, retinyl propionate, and retinyllinoleate. Retinoyl ester is an ester of retinoic acid with an alcohol.Suitable retinoyl esters include C₁-C₃₀ alcohol esters of retinoic acid,preferably C₂-C₂₀ esters and most preferably C₂-C₃ and C₁₆ esters. Someretinoyl esters comprise the linoleyl alcohol ester of retinoic acid,the hexanedecanol ester of retinoic acid, the oleic alcohol ester ofretinoic acid, retinoyl ascorbate, and the linolenyl alcohol ester ofretinoic acid.

While the compounds described herein can occur and can be used as theneutral (non-salt) compound, the description is intended to embrace allsalts of the compounds described herein, as well as methods of usingsuch salts of the compounds. In one embodiment, the salts of thecompounds comprise pharmaceutically acceptable salts and/ordermatologically acceptable salts. Pharmaceutically acceptable salts arethose salts which can be administered as drugs or pharmaceuticals tohumans and/or animals and which, upon administration, retain at leastsome of the biological activity of the free compound (neutral compoundor non-salt compound). Dermatologically acceptable salts are those saltswhich can be applied as drugs or pharmaceuticals to the skin of humansand/or animals and which, upon application, retain at least some of thebiological activity of the free compound (neutral compound or non-saltcompound). The desired salt of a basic compound may be prepared bymethods known to those of skill in the art by treating the compound withan acid. Examples of inorganic acids include, but are not limited to,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, andphosphoric acid. Examples of organic acids include, but are not limitedto, formic acid, acetic acid, propionic acid, glycolic acid, pyruvicacid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaricacid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelicacid, sulfonic acids, and salicylic acid. Salts of basic compounds withamino acids, such as aspartate salts and glutamate salts, can also beprepared. The desired salt of an acidic compound can be prepared bymethods known to those of skill in the art by treating the compound witha base. Examples of inorganic salts of acid compounds include, but arenot limited to, alkali metal and alkaline earth salts, such as sodiumsalts, potassium salts, magnesium salts, and calcium salts; ammoniumsalts; and aluminum salts. Examples of organic salts of acid compoundsinclude, but are not limited to, procaine, dibenzylamine,N-ethylpiperidine, N,N-dibenzylethylenediamine, and triethylamine salts.Salts of acidic compounds with amino acids, such as lysine salts, canalso be prepared. Other pharmaceutically acceptable salts are describedin Bighley, “Salt Forms of Drugs,” Encyclopedia of PharmaceuticalTechnology vol. 13 pp 453-499 (1996) (Swarbrick, Boylan, eds.), andBerge, “Pharmaceutical Salts,” J. Pharm. Sci. 66:1 (1977).

The invention also includes, if chemically possible, all stereoisomersof the compounds, including diastereomers and enantiomers. The inventionalso includes mixtures of possible stereoisomers in any ratio,including, but not limited to, racemic mixtures. Unless stereochemistryis explicitly indicated in a structure, the structure is intended toembrace all possible stereoisomers of the compound depicted. Ifstereochemistry is explicitly indicated for one portion or portions of amolecule, but not for another portion or portions of a molecule, thestructure is intended to embrace all possible stereoisomers for theportion or portions where stereochemistry is not explicitly indicated.

The compounds can be administered in prodrug form. Prodrugs arederivatives of the compounds, which are themselves relatively inactivebut which convert into the active compound when introduced into thesubject in which they are used by a chemical or biological process invivo, such as an enzymatic conversion. Suitable prodrug formulationsinclude, but are not limited to, peptide conjugates of the compounds ofthe invention and esters of compounds of the inventions. Furtherdiscussion of suitable prodrugs is provided in H. Bundgaard, Design ofProdrugs, New York: Elsevier, 1985; in R. Silverman, The OrganicChemistry of Drug Design and Drug Action, Boston: Elsevier, 2004; in R.L. Juliano (ed.), Biological Approaches to the Controlled Delivery ofDrugs (Annals of the New York Academy of Sciences, v. 507), New York:New York Academy of Sciences, 1987; and in E. B. Roche (ed.), Design ofBiopharmaceutical Properties Through Prodrugs and Analogs (Symposiumsponsored by Medicinal Chemistry Section, APhA Academy of PharmaceuticalSciences, November 1976 national meeting, Orlando, Fla.), Washington:The Academy, 1977.

The description of compounds herein also includes all isotopologues, forexample, partially deuterated or perdeuterated analogs of all compoundsherein.

Methods

Any of the compounds described herein can be mixed as cosmetics,cosmeceuticals, quasi-drugs (where applicable), or pharmaceutical drugs.The compounds can appropriately be mixed with other components. Examplesof such components include oily components such as hydrocarbons, fatsand oils such as liquid paraffin, squalene, petroleum jelly such asVaseline® (a registered trademark of Conopco Corp., Englewood Cliffs,N.J.), cetyl alcohol, isostearyl alcohol, cetyl-2-ethylhexanoate,2-octyldodecyl alcohol, glycerin, glycerin triisostearate, nut oils, andlanolin, as well as wax, silicone, surfactants, thickeners,neutralizers, antiseptics, germicides, anti-oxidants, powder components,pigments, perfumes, ultraviolet light absorbents, drugs, metallicsealant, and pH modifiers.

Occurrences in the skin of noticeable but undesired pigmentation as aresult of overproduction or underproduction of melanin or of noticeableuneven texture as a result of aging can be reduced, treated or preventedusing the methods described herein. Cosmetic applications for methodsdescribed herein include the topical application of compositionscontaining one or more of the compounds describe herein to enhance orotherwise alter the visual appearance of skin. The cosmetic compositionsdescribed herein are also useful to provide a smoother or softer skinappearance.

The active compounds described herein can also be used in combinationwith skin peeling agents (including glycolic acid or trichloroaceticacid face peels) or skin exfoliating agents (including retinoids, suchas retinoic acid or retinol) to lighten skin tone and preventrepigmentation. The appropriate dose regimen, the amount of each doseadministered, and specific intervals between doses of the activecompound will depend upon the particular active compound employed, thecondition of the patient or subject being treated, and the nature andseverity of the disorder or condition being treated. Preferably, theactive compound is administered in an amount and at an interval thatresults in the desired treatment of or improvement in the disorder orcondition being treated.

An active compound described herein can also be used in combination withsun screens (UVA or UVB blockers) to prevent repigmentation; to protectagainst sun or UV-induced skin darkening, or to enhance their skinlightening or bleaching action and to enhance their ability to reduceskin melanin. An active compound described herein can also be used incombination with any compounds that interact with retinoic acidreceptors and accelerate or enhance their ability to reduce skinmelanin, accelerate or enhance their skin lightening or bleachingaction, or accelerate or enhance their ability to prevent theaccumulation of skin melanin. An active compound described herein canalso be used in combination with 4-hydroxyanisole. An active compounddescribed herein can also be used in combination with ascorbic acid, itsderivatives and ascorbic-acid based products (such as magnesiumascorbate) or other products with an anti-oxidant mechanism (such asresveratrol, tocopherols, tocotrienols and derivatives) which accelerateor enhance their ability to reduce skin melanin, or accelerate orenhance their skin bleaching action.

In some variations, the composition further comprises a soybean extractthat is a blend of compounds isolated from soybean. The soybean extractmay contain only a portion of the soybean (e.g., an extract of thesoybean such as a lipid reduced soybean powder or filtered soymilk) ormay contain the entire soybean (e.g., a ground powder of the soybean).The soybean extract may be in the form of a fluid (e.g., soymilk) or asolid (e.g., a soybean powder or soymilk powder).

One or more active compounds used in the methods described herein may beused alone or in combination with one or more other compounds known inthe art. For example, any of the compounds described herein may be usedin combination with a tyrosinase inhibitor or other skin-lightening,pigmentation-modifying, or skin-whitening agent, including any one ormore of those agents, including compounds or extracts, described in thefollowing patent publications: U.S. Pat. No. 4,278,656 to Nagai et al.;U.S. Pat. No. 4,959,393 to Torihara et al.; U.S. Pat. No. 5,164,182;U.S. Pat. No. 5,580,549 to Fukuda et al.; U.S. Pat. No. 5,723,109 toL'Oreal; U.S. Pat. No. 6,123,959 to Jones et al.; U.S. Pat. No.6,132,740 to Hu; U.S. Pat. No. 6,159,482 to Tuloup et al.; U.S. Pat. No.6,365,135 to L'Oreal; U.S. Pat. No. 6,514,538 to Shiseido Co. Ltd.; U.S.Pat. Publ, No. 2006188559 to Neis; WO 99/64025 by Fytokem Prod. Inc.;U.S. Pat. No. 6,348,204 by L'Oreal; WO 00/56702 by Pfizer Inc.; JP5221846 by Kunimasa Tomoji; JP 7242687 by Shiseido Co. Ltd.; JP 7324023by Itogawa H.; JP 8012552 by Shiseido Co. Ltd.; JP 8012554 by ShiseidoCo. Ltd.; JP 8012557 by Shiseido Co. Ltd.; JP 8012560 by Shiseido Co.Ltd.; JP 8012561 by Shiseido Co. Ltd.; JP 8134090 by Fujisawa; JP8277225 by Kansai Koso K K; JP 9002967 by Sanki Shoji K K; JP 9295927 byYagi Akir; JP 10072330 by Kansai Kouso; JP 10081626 by Kamiyama K K; JP10101543 by Kansai Kouso K K; JP 11071231 by Maruzen Pharm.; JP 11079934by Kyodo Nyugyo; JP 11246347 by Shiseido Co. Ltd.; JP 11246344 byShiseido Co. Ltd.; JP 2000-080023 by Kanebo Ltd.; JP 2000-095663 by KoseK K; JP 2000-159681 by Hai Tai Confectionery Co. Ltd.; JP-7206753 byNikken Food K K; JP-59157009 by Yakurigaku Chuou K E; JP 2001019618, byShiseido; JP 2002029959 by Shiseido; JP 2004315534 by Access BusinessGroup Int Llc; JP 2005041821 by Shiseido; JP 2007063224 by KobayashiPharma; JP 2007091635 by Maruzen Pharma; JP 2008013481 by Univ. ofTokushima; KR 20040078449 by Enbioeng Co Ltd.; TW 281863 by TaiyenBiotech Co Ltd; and CN 101102746 by Young Chung Se; among others. Thesepatent publications are incorporated herein by reference in theirentireties.

Provided herein are methods of lightening or reducing the pigmentationof skin and/or of reducing uneven texture in which an active compounddescribed herein, and one or more of the other active ingredients, suchas those referred to above, are administered together as part of thesame pharmaceutical composition, as well as methods in which they areadministered separately as part of an appropriate dose regimen designedto obtain the benefits of the combination therapy. The appropriate doseregimen, the amount of each dose administered, and specific intervalsbetween doses of each active agent will depend upon the specificcombination of active agents employed, the condition of the patient orsubject being treated, and the nature and severity of the disorder orcondition being treated. Such additional active ingredients can beadministered in amounts less than or equal to those for which they areeffective as single topical therapeutic agents.

An active compound will generally be administered in the form of adermatological or cosmetic composition comprising the compound offormula I, together with a dermatologically acceptable carrier orsolvent. Alternatively, an active compound can be administered in theform of a pharmaceutical composition comprising the compound of formulaI, together with a pharmaceutically acceptable carrier or solvent.

In the depigmenting compositions provided herein, the concentration ofthe active compound is generally between 0.01% and 10%, or between about0.01% and about 10%, for example between 0.1% and 5% or between about0.1% and about 5%, or between 0.1% and 2%, or between about 0.1% andabout 2%, or between 0.1% and 1%, or between about 0.1% and about 1%,relative to the total weight of the composition.

The compositions described herein can be applied directly to the skin.Alternatively, they can be delivered by various transdermal drugdelivery systems, such as transdermal patches as known in the art. Forexample, for topical administration, the active ingredient can beformulated in a solution, gel, lotion, ointment, cream, suspension,paste, liniment, powder, tincture, aerosol, patch, or the like in apharmaceutically or cosmetically acceptable form by methods known in theart. The composition can be any of a variety of forms common in thepharmaceutical or cosmetic arts for topical application to animals orhumans, including solutions, lotions, sprays, creams, ointments, salves,gels, etc., as described below. Exemplary agents are those that areviscous enough to remain on the treated area, those that do not readilyevaporate, and/or those that are easily removed by rinsing with water,optionally with the aid of soaps, cleansers and/or shampoos. Actualmethods for preparing topical formulations are known to those skilled inthe art, such as those described in Remington's Pharmaceutical Sciences,(1990); and Pharmaceutical Dosage Forms and Drug Delivery Systems, 6thed., Williams & Wilkins (1995).

The compositions may be made into a wide variety of product types thatinclude but are not limited to solutions, suspensions, lotions, creams,gels, toners, sticks, sprays, ointments, cleansing liquid washes andsolid bars, shampoos and hair conditioners, pastes, foams, powders,mousses, shaving creams, wipes, strips, patches, electrically-poweredpatches, wound dressing and adhesive bandages, hydrogels, film-formingproducts, facial and skin masks, make-up such as foundations, eyeliners, and eye shadows, and the like. These product types may containseveral types of cosmetically-acceptable carriers including, but notlimited to solutions, suspensions, emulsions such as microemulsions andnanoemulsions, gels, solids and liposomes.

The compositions can be formulated as solutions. Solutions typicallyinclude an aqueous or organic solvent, e.g., from about 50% to about99.99% or from about 90% to about 99% of a cosmetically acceptableaqueous or organic solvent. Examples of suitable organic solventsinclude: propylene glycol, polyethylene glycol (200-600), polypropyleneglycol (425-2025), glycerol, 1,2,4-butanetriol, sorbitol esters,1,2,6-hexanetriol, ethanol, and mixtures thereof. One example of suchsolvents is a mixture of ethanol/polyethylene glycol (80/20).

A lotion can be made from such a solution. Lotions typically containfrom about 1% to about 20% (e.g., from about 5% to about 10%) of anemollient(s) and from about 50% to about 90% (e.g., from about 60% toabout 80%) of water.

Another type of product that may be formulated from a solution is acream. A cream typically contains from about 5% to about 50% (e.g., fromabout 10% to about 20%) of an emollient(s) and from about 45% to about85% (e.g., from about 50% to about 75%) of water.

Yet another type of product that may be formulated from a solution is anointment. An ointment may contain a simple base of animal, vegetable, orsynthetic oils or semi-solid hydrocarbons. An ointment may contain fromabout 2% to about 10% of an emollient(s) plus from about 0.1% to about2% of a thickening agent(s). Examples of thickening agents include, butare not limited to, those set forth in the ICI Handbook (InternationalCosmetic Ingredient Dictionary and Handbook) pp. 1693-1697.

The compositions described herein can also be formulated as emulsions.If the carrier is an emulsion, from about 1% to about 10% (e.g., fromabout 2% to about 5%) of the carrier contains an emulsifier(s).Emulsifiers may be nonionic, anionic or cationic. Examples ofemulsifiers include, but are not limited to, those set forth in the ICIHandbook, pp. 1673-1686.

Lotions and creams can be formulated as emulsions. Typically suchlotions contain from 0.5% to about 5% of an emulsifier(s), while suchcreams would typically contain from about 1% to about 20% (e.g., fromabout 5% to about 10%) of an emollient(s); from about 20% to about 80%(e.g., from 30% to about 70%) of water; and from about 1% to about 10%(e.g., from about 2% to about 5%) of an emulsifier(s).

Single emulsion skin care preparations, such as lotions and creams, ofthe oil-in-water type and water-in-oil type are well-known in the artand are useful in compositions and methods described herein. Multiphaseemulsion compositions, such as the water-in-oil-in-water type or theoil-in-water-in-oil type, are also useful in the compositions andmethods describe herein. In general, such single or multiphase emulsionscontain water, emollients, and emulsifiers as essential ingredients.

The compositions described herein can also be formulated as a gel (e.g.,an aqueous, alcohol, alcohol/water, or oil gel using a suitable gellingagent(s)). Suitable gelling agents for aqueous and/or alcoholic gelsinclude, but are not limited to, natural gums, acrylic acid and acrylatepolymers and copolymers, and cellulose derivatives (e.g., hydroxymethylcellulose and hydroxypropyl cellulose). Suitable gelling agents for oils(such as mineral oil) include, but are not limited to, hydrogenatedbutylene/ethylene/styrene copolymer and hydrogenatedethylene/propylene/styrene copolymer. Such gels typically containsbetween about 0.1% and 5%, by weight, of such gelling agents.

One or more additional agents can be added in the topical formulationsin order to enhance the percutaneous absorption of the activeingredients, including, but not limited to, dimethylsulfoxide,dimethylacetamide, dimethylformamide, surfactants, azone (laurocapram),alcohol, acetone, propylene glycol and polyethylene glycol. Physicalmethods can also be used to enhance transdermal penetration such asiontophoresis or sonophoresis. Alternatively, or in addition,administration via liposomes can be employed.

A topically applied composition provided herein contains apharmaceutically effective agent that has the desired effect on skin asdescribed herein, and those ingredients as are necessary for use as acarrier, such as an emulsion, a cream, an ointment, an aqueous solution,a lotion or an aerosol. Non-limiting examples of such carriers may befound in U.S. Pat. No. 5,691,380 to Mason et al., issued Nov. 25, 1997;and U.S. Pat. No. 5,968,528 to Deckner et al., issued Oct. 19, 1999;which are incorporated herein by reference. Suitable pharmaceuticalcarriers are further described in Remington's Pharmaceutical Sciences,17th ed., Mack Publishing Company, Easton, Pa. (1990).

The carrier utilized in the compositions described herein can be in awide variety of forms. These include emulsion carriers, including, butnot limited to, oil-in-water, water-in-oil, water-in-oil-in-water, andoil-in-water-in-silicone emulsions, a cream, an ointment, an aqueoussolution, a lotion or an aerosol. As will be understood by the skilledartisan, a given component will distribute primarily into either thewater or oil/silicone phase, depending on the watersolubility/dispersibility of the component in the composition.

Dermatological formulations provided herein may typically comprise aderivative of any compound or composition described herein andoptionally, a polar solvent. Solvents suitable for use in theformulations described herein include any polar solvent capable ofdissolving the derivative. Suitable polar solvents may include: water;alcohols (such as ethanol, propyl alcohol, isopropyl alcohol, hexanol,and benzyl alcohol); polyols (such as propylene glycol, polypropyleneglycol, butylene glycol, hexylene glycol, maltitol, sorbitol, andglycerine); and panthenol dissolved in glycerine, flavor oils andmixtures thereof. Mixtures of these solvents can also be used. Exemplarypolar solvents may be polyhydric alcohols and water. Examples ofsolvents may include glycerine, panthenol in glycerine, glycols such aspropylene glycol and butylene glycol, polyethylene glycols, water andmixtures thereof. Additional polar solvents for use may be alcohols,glycerine, panthenol, propylene glycol, butylene glycol, hexylene glycoland mixtures thereof.

An emollient may also be added to the cosmetic/dermatologicalcompositions described herein. The emollient component can comprisefats, oils, fatty alcohols, fatty acids and esters which aid applicationand adhesion, yield gloss and provide occlusive moisturization. Suitableemollients for use may be isostearic acid derivatives, isopropylpalmitate, lanolin oil, diisopropyl dimerate, maleated soybean oil,octyl palmitate, isopropyl isostearate, cetyl lactate, cetylricinoleate, tocopheryl acetate, acetylated lanolin alcohol, cetylacetate, phenyl trimethicone, glyceryl oleate, tocopheryl linoleate,wheat germ glycerides, arachidyl propionate, myristyl lactate, decyloleate, propylene glycol ricinoleate, isopropyl linoleate,pentaerythrityl tetrastearate, neopentylglycol dicaprylate/dicaprate,hydrogenated coco-glycerides, isononyl isononanoate, isotridecylisononanoate, myristyl myristate, triisocetyl citrate, cetyl alcohol,octyl dodecanol, oleyl alcohol, panthenol, lanolin alcohol, linoleicacid, linolenic acid, sucrose esters of fatty acids, octylhydroxystearate and mixtures thereof. Examples of other suitableemollients can be found in the Cosmetic Bench Reference, pp. 1.19-1.22(1996), or in the International Cosmetic Ingredient Dictionary andHandbook, eds. Wenninger and McEwen, pp. 1656-61, 1626, and 1654-55 (TheCosmetic, Toiletry, and Fragrance Assoc., Washington, D.C., 7.sup.thEdition, 1997) (hereinafter “ICI Handbook”), incorporated herein byreference. Suitable emollients may include polar emollient emulsifiers(such as linear or branched chained polyglycerol esters) and non-polaremollients. The emollient component typically may comprise from about 1%to about 90%, preferably from about 10% to about 80%, more preferablyfrom about 20% to about 70%, and most preferably from about 40% to about60%, of the cosmetic composition.

By “polar emollient,” as used herein, is meant any emollient emulsifierhaving at least one polar moiety and wherein the solubility (at 30° C.)of the cytoprotective derivative compound in the polar emollient isgreater than about 1.5%, preferably greater than about 2%, morepreferably greater than about 3%. Suitable polar emollients may include,but are not limited to, polyol ester and polyol ethers such as linear orbranched chained polyglycerol esters and polyglycerol ethers.Non-limiting examples of such emollients may include PG3 diisostearate,polyglyceryl-2-sesquiisostearate, polyglyceryl-5-distearate,polyglyceryl-10-distearate, polyglyceryl-10-diisostearate, acetylatedmonoglycerides, glycerol esters, glycerol tricaprylate/caprate, glycerylricinoleate, glyceryl isostearate, glyceryl myristate, glyceryllinoleate, polyalkylene glycols such as PEG 600, monoglycerides,2-monolaurin, sorbitan esters and mixtures thereof.

By “non-polar emollient,” as used herein, means any emollient emulsifierpossessing no or minimal permanent electric moments. Suitable non-polaremollients may include, but are not limited to, esters and linear orbranched chained hydrocarbons. Non-limiting examples of such emollientsmay include isononyl isononanoate, isopropyl isostearate, octylhydroxystearate, diisopropyl dimerate, lanolin oil, octyl palmitate,isopropyl palmitate, paraffins, isoparaffins, acetylated lanolin,sucrose fatty acid esters, isopropyl myristate, isopropyl stearate,mineral oil, silicone oils, dimethicone, allantoin, isohexadecane,isododecane, petrolatum, and mixtures thereof. The solubility of thecompound in polar or non-polar emollients may be determined according tomethods known in the art.

Suitable oils include esters, triglycerides, hydrocarbons and silicones.These can be a single material or a mixture of one or more materials.They may normally comprise from 0.1% to about 100%, preferably fromabout 5% to about 90%, and most preferably from about 70% to about 90%of the emollient component.

Oils that act as emollients also impart viscosity, tackiness, and dragproperties to cosmetic compositions such as lipstick. Examples ofsuitable oils may include acrylic triglycerides; caprice triglyceride;isostearyl triglyceride; atopic triglyceride; propylene glycol myristylacetate; lanolin; lanolin oil; polybutene; isopropyl palmitate;isopropyl myristate; isopropyl isostearate; diethyl sebacate;diisopropyl adipate; tocopheryl acetate; tocopheryl linoleate; hexadecylstearate; ethyl lactate; cetyl oleate; cetyl ricinoleate; oleyl alcohol;hexadecyl alcohol; octyl hyroxystearate; octyl dodecanol; wheat germoil; hydrogenated vegetable oils; castor oil; petrolatum; modifiedlanolins; branched-chain hydrocarbons; alcohols and esters; corn oil;cottonseed oil; olive oil; palm kernel oil; rapeseed oil; safflower oil;jojoba oil; evening primrose oil; avocado oil, mineral oil, shea butter,octylpalmitate, maleated soybean oil, glycerol trioctanoate, diisopropyldimerate, and volatile and non-volatile silicone oils including phenyltrimethicone.

Suitable oils for use herein may be acetylglycerides, octanoates, anddecanoates of alcohols and polyalcohols, such as those of glycol andglycerol, the ricinoleates of alcohols and polyalcohols such as cetylricinoleate, PG-3 diisostearate, polyglycerol ethers, polyglyerolesters, caprylic triglycerides, capric triglycerides, isostearictriglyceride, adipic triglyceride, phenyl trimethicone, lanolin oil,polybutene, isopropyl palmitate, isopropyl isostearate, cetylricinoleate, octyl dodecanol, oleyl alcohol, hydrogenated vegetableoils, castor oil, modified lanolins, octyl palmitate, lanolin oil,maleated soybean oil, cetyl ricinoleate, glyceryl trioctanoate,diisopropyl dimerate, synthetic lanolin derivatives and branched chainalcohols, sucrose esters of fatty acids, octyl hydroxystearate andmixtures thereof.

Preferably, the oils used may be selected such that the majority (atleast about 75%, preferably at least about 80% and most preferably atleast about 99%) of the types of oils used have solubility parametersthat do not differ by more than from about 1 to about 0.1, preferablyfrom about 0.8 to about 0.1.

A surfactant may also be added to compositions described herein, inorder to confer beneficial cosmetic or application properties.Surfactants suitable for use may be those which can form emulsionsand/or association structures. Surfactant emulsifier can be from 0% toabout 20% of the formulation, preferably from 0% to about 15% and mostpreferably from about 1% to about 10%. Examples of suitable emulsifierscan be found in U.S. Pat. No. 5,085,856 to Dunphy et al., and U.S. Pat.No. 5,688,831 to El-Nokaly et al. Examples of other suitable emulsifierscan be found in Cosmetic Bench Reference, pp. 1.22, 1.24-1.26 (1996),all of which are incorporated herein by reference.

Examples of surface active agents which may be used in the compositionsdescribed herein include sodium alkyl sulfates, e.g., sodium laurylsulfate and sodium myristyl sulfate, sodium N-acyl sarcosinates, e.g.,sodium N-lauroyl sarcosinate and sodium N-myristoyl sarcosinate, sodiumdodecylbenzenesulfonate, sodium hydrogenated coconut fatty acidmonoglyceride sulfate, sodium lauryl sulfoacetate and N-acyl glutamates,e.g., N-palmitoyl glutamate, N-methylacyltaurin sodium salt,N-methylacylalanine sodium salt, sodium alpha-olefin sulfonate andsodium dioctylsulfosuccinate; N-alkylaminoglycerols, e.g.,N-lauryl-diamino-ethylglycerol and N-myristyldiaminoethylglycerol,N-alkyl-N-carboxymethylammonium betaine and sodium2-alkyl-1-hydroxyethylimidazoline betaine; polyoxyethylenealkyl ether,polyoxyethylenealkylaryl ether, polyoxyethylenelanolin alcohol,polyoxyethyleneglyceryl monoaliphatic acid ester,polyoxyethylenesorbitol aliphatic acid ester, polyoxyethylene aliphaticacid ester, higher aliphatic acid glycerol ester, sorbitan aliphaticacid ester, Pluronic type surface active agent, andpolyoxyethylenesorbitan aliphatic acid esters such aspolyoxyethylenesorbitan monooleate and polyoxyethylenesorbitanmonolaurate. Emulsifier-type surfactants known to those of skill in theart can be used in the compositions described herein.

Also useful herein may be surfactants that form association structures,preferably lamellar or hexagonal liquid crystals, at ambient temperaturewhen mixed with a polar solvent. In preparing a sample combination ofsurfactant and polar solvent to demonstrate the ability to formassociation structures, the surfactant needs to be sufficiently solublein the polar solvent such that an association structure can form atambient temperature. One of ordinary skill in the art is capable ofdetermining compatible interactions.

Any surfactant which forms association structures at ambient temperatureand is suitable for use in cosmetics may be suitable for use herein.Surfactants suitable for use in cosmetics present no or minimaldermatological or toxicological problems. Anionic surfactants, nonionicsurfactants, cationic surfactants, amphoteric surfactants and mixturesthereof may be suitable for use. Preferably anionic surfactants,nonionic surfactants, cationic surfactants, amphoteric surfactants andmixtures thereof having a Krafft point at or below about ambienttemperature are used. More preferably, nonionic surfactants, cationicsurfactants, amphoteric surfactants and mixtures thereof having a Krafftpoint at or below about ambient temperature are used.

The surfactants can be used at levels from about 4% to about 97%,preferably from about 5% to about 95%, more preferably from about 20% toabout 90% and most preferably from about 30% to about 70% of theassociation structure.

The cosmetic compositions described herein may contain one or morematerials, herein singly or collectively referred to as a “solidifyingagent”, that are effective to solidify the particular liquid basematerials to be used in a cosmetic composition. (As used herein, theterm “solidify” refers to the physical and/or chemical alteration of theliquid base material so as to form a solid or semi-solid at ambientconditions, i.e., to form a final composition that has a stable physicalstructure and can be deposited on the skin under normal use conditions.)As is appreciated by those skilled in the art, the selection of theparticular solidifying agent for use in the cosmetic compositions willdepend upon the particular type of composition desired, i.e., gel orwax-based, the desired rheology, the liquid base material used and theother materials to be used in the composition. The solidifying agent canbe preferably present at a concentration of from about 0.1% to about90%, more preferably from about 1% to about 50%, even more preferablyfrom about 5% to about 40%, most preferably from about 3% to about 20%.

The wax cosmetic stick variations provided herein preferably may containfrom about 5% to about 50% (by weight) of a waxy solidifying agent. Bythe term “waxy solidifying agent,” as used herein, is meant asolidifying material having wax-like characteristics. Such waxymaterials may also serve as emollients. Among the waxy materials usefulherein are the high melting point waxes, i.e., having a melting point offrom about 65° C. to about 125° C., such as beeswax, spermaceti,carnauba, bayberry, candelilla, montan, ozokerite, ceresin, paraffin,synthetic waxes such as Fisher-Tropsch waxes, microcrystalline wax, andmixtures thereof. Ceresin, ozokerite, white beeswax, synthetic waxes,and mixtures thereof, are among those useful herein; additional usefulwaxes are disclosed in U.S. Pat. No. 4,049,792, Elsnau, issued Sep. 20,1977, herein incorporated by reference in its entirety. Low meltingwaxes, having a melting point of from about 37° C. to about 75° C., maybe preferred for use in the wax stick variations described herein. Waxstick variations, which contain volatile silicone oils as a liquid basematerial, preferably contain from about 10% to about 35%, morepreferably from about 10% to about 20% (by weight), of a low-meltingwax. Such materials include fatty acids, fatty alcohols, fatty acidesters and fatty acid amides, having fatty chains of from about 8 toabout 30 carbon atoms, and mixtures thereof. Wax-like materials includecetyl alcohol, palmitic acid, stearyl alcohol, behenamide, sucroseesters of tallow fatty acids, mono and di-fatty acid esters ofpolyethylene glycol, and mixtures thereof. Stearyl alcohol, cetylalcohol, and mixtures thereof, are mostly used. Additional fatty acids,fatty alcohols, and other wax-like materials are also well known in theart.

In addition, these compositions may include other medicinal agents,therapeutic agents, carriers, adjuvants, and the like. Some particularadditional agents may include sunscreens; retinoids; antioxidants;hydroxyacids; fatty acids, acceptable non-toxic metal salts of naturallyoccurring amino acids or of hydroxyalkyl acids; botanical extracts,salicylic acid, benzoyl peroxide, antibiotics, antiandrogens,anti-inflammatory agents, antioxidants, ascorbic acid, vitamins B,tocopherols or tocotrienols, corticosteroids, moisteners, surfactants,keratolytic agents, complexing agents, colorants, fragrances, andmixtures thereof.

Measurement of Skin Pigmentation and Coloration

Measurements of skin pigmentation and coloration can be quantitatedusing a chromameter, colorimeter, or skin reflectance instrument (see,for example, Clarys et al., Skin Res. Technol. 6(4):230-238 (2000)).Chromameters are commercially available from vendors such as KonicaMinolta (CR-400 or CR-410 Chroma Meter) or Gigahertz-Optik (HCT-99Dcolor meter). Baseline readings prior to treatment are taken, andreadings during treatment can be taken, at one or more wavelengths. Skincoloration can be measured and compared to assess treatment.Measurements can be taken at various points, such as an area affected bydiscoloration and a surrounding unaffected area.

Synthetic Methods

The resorcinol compounds described herein can be synthesized by anappropriate combination of generally well-known synthetic methods.Techniques useful in synthesizing the compounds herein are both readilyapparent and accessible to those of skill in the relevant art in lightof the teachings described herein. The discussion below is offered toillustrate certain of the diverse methods available for use inassembling the compounds herein. However, the discussion is not intendedto limit the scope of reactions or reaction sequences that are useful inpreparing the compounds herein.

The resorcinol compounds described herein may be synthesized accordingto Scheme 1. Reactant C(O)R² indicates a reactant having a carbonylgroup; that is, the C═O group is a part of R², and not an additionalmoiety appended to R². Appropriate protecting groups (PG in the schemebelow), such as alkyl groups, may be used to protect certain functionalgroups from reaction conditions, and such protecting groups are removedunder standard conditions when appropriate.

Scheme 2 shows an exemplary synthesis of a 5-methyl resorcinol compounddescribed herein according to Scheme 1. R^(a) and R^(b) are eachhydrogen or substituted or unsubstituted alkyl, wherein the substitutedor unsubstituted alkyl groups may be the same or different, or R^(a) andR^(b), together with the carbon to which they are attached, form asubstituted or unsubstituted cycloalkyl. Compound 1 (commerciallyavailable from Sigma-Aldrich, St. Louis, Mo.) is brominated, for examplewith N-bromosuccinimide, to afford compound 2, which is reacted withmagnesium to form Grignard reagent 3. Compound 3 is reacted with analkyl ketone in the presence of lanthanum salts, followed by reductionby hydrogen over Pd/C to form compound 4. The alkoxy groups are thenconverted to hydroxy groups to afford resorcinol compound 5.

Scheme 3 shows an exemplary synthesis of a 5-fluoro resorcinol compounddescribed herein according to Scheme 1. R^(c) and R^(d) are eachhydrogen or substituted or unsubstituted alkyl, wherein the substitutedor unsubstituted alkyl groups may be the same or different, or R^(c) andR^(d), together with the carbon to which they are attached, form asubstituted or unsubstituted cycloalkyl. Compound 6 (commerciallyavailable from Sigma-Aldrich, St. Louis, Mo.) is brominated to affordcompound 7, which is reacted with magnesium to form Grignard reagent 8.Compound 8 is reacted with an alkyl ketone in the presence of lanthanumsalts to form compound 9, followed by reduction by hydrogen over Pd/C toform compound 10. The alkoxy groups are then converted to hydroxy groupsto afford resorcinol compound 11. Similar methods can be used tosynthesize other 4-halo resorcinols.

Scheme 4 shows an exemplary synthesis of a 4-alkyl-5-trifluoromethylresorcinol compound described herein according to Scheme 1. R^(e) issubstituted or unsubstituted alkyl. Bromide compound 12 is converted tothe corresponding iodide 13, which is reacted with an acyl chloride toform ketone 14. Compound 14 is reacted withdifluoro-fluorosulfonyl-acetic acid methyl ester (15) to form compound16, followed by reduction by zinc in the presence of acid (or othersuitable reducing agent) to form compound 17. The alkoxy groups are thenconverted to hydroxy groups to afford resorcinol compound 18. Similarmethods can be used to synthesize other 4-alkyl-5-trifluoromethylresorcinols.

Scheme 5 shows an exemplary synthesis of a4-cycloalkyl-5-trifluoromethyl resorcinol compound described hereinaccording to Scheme 1. A represents a substituted or unsubstitutedcycloalkenyl ring, and B represents the corresponding substituted orunsubstituted cycloalkyl ring. Bromide compound 19 is converted to thecorresponding iodide 20. Compound 20 is reacted withdifluoro-fluorosulfonyl-acetic acid methyl ester to form compound 21,followed by bromination with NBS to form compound 22. Cycloalkenyl A isinstalled using an appropriate dioxaborolane to form compound 23, whichis reduced in the presence of Pd/C (or other suitable reducing agent) toform compound 24. The alkoxy groups are then converted to hydroxy groupsto afford resorcinol compound 25. Similar methods can be used tosynthesize other 4-cycloalkyl-5-trifluoromethyl resorcinols.

EXAMPLES Example 1 4-cyclohexyl-5-methylbenzene-1,3-diol (4,5CHMR)

4-bromo-1,5-bis(methoxymethoxy)-3-methylbenzene. 26.10 g of orcinol and19.10 g of ammonium bromide were weighed into a 2000 mL 3-neck roundbottom flask fitted with a stir bar, thermometer, and nitrogen bubbler.A nitrogen atmosphere was established and maintained. 1000 mL ofacetonitrile was added, and the mixture was stirred rapidly to suspendthe solids. The suspension was cooled to 10° in an ice bath and 67.88 gof Oxone™ (OXONE is a registered trademark of DuPont for amonopersulfate oxidizing compound) was added in one portion. The icebath was removed, and the mixture was stirred at 20° for 30 h. Thesolids were removed by filtration. The solvent was removed from thefiltrate to obtain a dark orange solid. The solid was partitionedbetween 200 mL of 1.0 M hydrochloric acid and 400 mL tert-butyl methylether. The phases were separated, and the aqueous phase was extractedwith 200 mL tert-butyl methyl ether. The combined organic phases werewashed with 5×200 mL of 1.0 M pH 5.5 phosphate buffer and 200 mL ofbrine. 1.0 g of activated carbon was added to the solution, and thesolution was dried over sodium sulfate. The solution was filteredthrough a 10 cm diameter Buchner funnel containing a 2-layer filter padof 5 cm silica gel on top of 2 cm of Celite™ (CELITE is a registeredtrademark of Imerys Minerals California, Inc. for a diatomaceousearth-containing filter aid). The filter pad was washed with 2×300 mL oftert-butyl methyl ether. The solvent was removed from the filtrate toobtain 38.78 g of a brown-orange solid. The solid was recrystallizedfrom 1,2-dichloroethane and dried under vacuum to obtain 35.30 g of a7:88:4 mixture of unbrominated:monobrominated:dibrominated orcinols asbrown crystals. 32.95 g of the crystals were dissolved in 100 mL ofanhydrous ethyl acetate, and the solution was added dropwise to asolution of chloromethyl methyl ether prepared as described below.

A three-necked 1000-mL flask was fitted with a magnetic stir bar,thermometer, addition funnel, efficient reflux condenser with nitrogeninlet, and gas outlet bubbler quenched into 1.0 M aqueous sodiumhydroxide. A nitrogen atmosphere was established and maintained. Theflask was charged with 46.65 g of dimethoxymethane and 180 mL ofanhydrous toluene. 16 mg of zinc bromide was added. 47.2 g of acetylchloride was added dropwise over 10 minutes. The addition funnel wasrinsed with 20 mL of toluene directly into the reaction mixture. Thereaction mixture was stirred at 20° for 4.5 h. The resulting solution ofchloromethyl methyl ether was cooled with an ice bath, and 100 mL ofN,N-diisopropylethylamine was added dropwise over 20 min. The solutionof 32.95 g of brominated orcinols in 100 mL ethyl acetate prepared abovewas added dropwise at a rate to maintain the reaction temperature below10°. A white precipitate formed during the addition. The ice bath wasremoved, and the mixture was stirred at 20° for 68 h. The reaction wasquenched with 100 mL of saturated aqueous ammonium chloride. 50 mL ofwater was added to bring all the salts into solution. The biphasicmixture was stirred vigorously for 3 h to ensure all residualchloromethyl methyl ether was decomposed. The phases were separated, andthe aqueous phase was extracted with 250 mL of ethyl acetate. Thecombined organic phases were washed with 2×200 mL of 1.0 M aqueouscitric acid, 3×200 mL of 1.0 M aqueous sodium hydroxide, and 250 mL ofbrine. The solution was dried over sodium sulfate and the solvent wasremoved to obtain 47.87 g of a red liquid. 45.34 g of the crude waspurified by vacuum distillation to obtain 35.91 g [86% yield calculatedfrom orcinol] of the title compound as a pale yellow liquid, Bp92-94°/0.046 Torr. ¹H-NMR (400 MHz, CDCl₃) δ 6.69 (d, J=2.7 Hz), 6.64(d, J=2.7 Hz), 5.20 (s, 2H), 5.11 (s, 2H), 3.50 (s, 3H), 3.45 (s, 3H),2.37 (s, 3H).

4-cyclohexyl-1,5-bis(methoxymethoxy)-3-methylbenzene

1.12 g of 2-dicyclohexylphosphino-2′,6′-bis(N,N-dimethylamino)biphenyl,0.28 g of palladium(II)acetate, and 18.50 g of4-bromo-1,5-bis(methoxymethoxy)-3-methylbenzene (1) were weighed into a1000 mL oven dried 3-neck round bottom flask fitted with a stir bar,thermometer, addition funnel, and nitrogen bubbler. A nitrogenatmosphere was established and maintained. 200 mL of anhydrous THF wasadded, and the mixture was stirred to obtain a clear ruby solution. Thesolution was cooled with an ice bath, 150 mL of a 0.5 M solution ofcyclohexylzinc bromide in THF was added over 60 min, keeping thereaction temperature below 5° C. The cooling bath was removed when theaddition was complete, and the mixture was stirred at ambienttemperature for 4 h. The solution was cooled in an ice bath and quenchedwith 350 mL of saturated aqueous ammonium chloride. The phases wereseparated, and the aqueous phase was extracted with 350 mL ofcyclopentyl methyl ether. The combined organic phases were filteredthrough Celite™ to remove fine particulates. The filtrate was washedwith 2×300 mL of 1.0 M citric acid, 300 mL of saturated aqueous sodiumbicarbonate, and 300 mL of brine, and dried over sodium sulfate andremoved the solvent to obtain a dark red liquid. The liquid was dilutedwith 100 mL of heptane and filtered through a 5 cm thick×9.5 cm diametersilica gel pad. The product was washed through with 1000 mL of 25%EtOAc/heptane. The solvent was removed from the filtrate. The amberliquid was purified by vacuum distillation to obtain 15.83 g [85% yield]of the title compound as a clear colorless oil, Bp 114-116° C./0.056Torr. ¹H-NMR (400 MHz, CDCl₃) δ 6.63 (d, J=2.5 Hz), 6.49 (d, J=2.5 Hz),5.13 (s, 2H), 5.10 (s, 2H), 3.47 (s, 3H), 3.45 (s, 3H), 2.77 (br s, 1H),2.29 (s, 3H), 2.10-1.95 (m, 2H), 1.83-1.75 (m, 2H), 1.73-1.66 (m, 1H),1.59-1.52 (m, 2H), 1.37-1.18 (m, 3H).

4-cyclohexyl-5-methylbenzene-1,3-diol (4,5CHMR)

15.78 g of 4-cyclohexyl-1,5-bis(methoxymethoxy)-3-methylbenzene (2) wasweighed into an oven dried 1000 mL flask fitted with a stir bar, septumand nitrogen bubbler. A nitrogen atmosphere was established andmaintained. Added 400 mL of anhydrous methanol. Cooled the solutionbelow 5° C. Added 7.7 mL of acetyl chloride over 30 min, keeping thereaction temperature below 5° C. Removed the cooling bath when theaddition was complete and stirred at 20° C. for 42 h. Removed thevolatiles on a rotary evaporator to obtain a yellow resin. Dissolved theresin in 75 mL MTBE and diluted with 75 mL heptane. Removed baselineimpurities by passing the solution through 220 g of silica gel, washingthe product through with 800 mL of 50% MTBE/heptane. Removed the solventon a rotary evaporator to obtain a pale yellow solid. The solid wasrecrystallized twice from 50 mL of 1,2-dichloroethane. Dried undervacuum at 85°/0.05 Torr to obtain 9.33 g [84% yield] of the titlecompound as fine white needles. 300 mg of this material was purified bysublimation at 130°/0.03 Torr to obtain an analytical standard. ¹H-NMR(400 MHz, DMSO-d₆) δ 8.74 (overlapping singlets, 2H), 6.07 (d, J=2.5Hz), 5.98 (d, J=2.4 Hz), 2.64 (br s, 1H), 2.17-1.98 (methyl singlet at2.12 overlaps multiplet, 5H), 1.77-1.68 (m, 2H), 1.68-1.60 (m, 1H),1.46-1.34 (m, 2H), 1.34-1.10 (m, 3H).

Example 2 4-cyclohexyl-5-fluorobenzene-1,3-diol (4,5CHFR)

2-bromo-1-fluoro-3,5-dimethoxybenzene

28.22 g of 3,5-dimethoxy-5-fluorobenzene was weighed into a 1,000 mLround bottom flask fitted with a stir bar, reflux condenser, nitrogeninlet, and cap. A nitrogen atmosphere was established and maintainedthroughout the reaction. 200 mL of anhydrous CCl₄ was added, followed by32.61 g of N-bromosuccinimide (NBS). The remaining NBS powder residuewas washed into the flask with 100 mL of CCl₄. The reaction mixture wasstirred at reflux under N, for 4 h, during which time the suspendedyellow solids changed color to white. At completion, the precipitatedsuccinimide solids were filtered off and washed thoroughly with 200 mLheptane. The CCl₄ was removed from the filtrate by rotary evaporation at50° C. More succinimide precipitated from the heptane solution and wasremoved by filtration while the solution was still warm. The remainingheptane was removed in vacuo to obtain a clear, amber oil (40.67 g),which solidified on standing. Purification of the crude material wasaccomplished by distillation. The condenser was kept at 50° C. toprevent the product from solidifying before reaching the collectionflask. After a small impurity fraction was collected at 78° C./8 torr,the product distilled at 123-125° C./8 torr. The clear pale yellowliquid solidified to an off-white solid on standing (37.88 g, 89%).

1-(2-fluoro-4,6-dimethoxyphenyl)cyclohexanol

19.52 g of 2-bromo-1-fluoro-3,5-dimethoxybenzene was weighed into anoven-dried 500 mL round bottom flask fitted with a stir bar, septum,thermometer, and nitrogen inlet. A nitrogen atmosphere was establishedand maintained. To the solution was slowly added 200 mL of a 0.5 Msolution of lithium chloride in anhydrous THF. The clear pale yellowsolution was placed in a water ice/acetone bath and the reactiontemperature was maintained between −15° C. and −10° C. To the reactionmixture was added 45 mL of a 2.0 M (iodometric titration) solution ofisopropyl magnesium chloride in diethyl ether, dropwise over 20 minusing a syringe pump. The reaction was stirred between −20° C. and −15°C. for 60 min. The solution rapidly became colorless at the start ofaddition, then slowly became a clear yellow color. LC-MS analysis of analiquot quenched in 5% H₂O/MeOH at 60 min indicated the reaction was 50%complete. At this point, 5 mL of a 2.0 M solution of isopropylmagnesiumchloride in Et₂O was added via syringe. LC-MS analysis of an aliquotquenched in 5% H₂O/MeOH 60 min after the addition indicated the reactionwas 80% complete. After waiting another 30 min, the clear yellowsolution was transferred into the next reaction via cannula.

7.48 g of cyclohexanone was weighed into an oven-dried 1,000 mL 3-neckround bottom flask fitted with a stir bar, septum, thermometer, andnitrogen inlet. A nitrogen atmosphere was established and maintained. Tothe solids was added 125 mL of a 0.6 M solution of lanthanum trichloridecomplex with 2 equivalents of lithium chloride in anhydrous THF. Thesolution was stirred at room temperature for 2.5 h. Following thisperiod, the clear amber solution was cooled in a water ice/acetone bathand the solution temperature was maintained between −5° C. and 0° C.during addition. The above-described solution of2,4-dimethoxy-6-methylphenyl magnesium chloride complex with lithiumchloride was transferred into the reaction mixture by cannula. The amberreaction mixture was stirred between 0° C. and 5° C. for 2 h. Thereaction mixture was cooled to −10° and quenched by adding a mixture of100 g of ice in 100 mL of saturated aqueous NH₄Cl. A moderate exothermraised the temperature to 5° C. before cooling down again. A whiteemulsion formed in the aqueous layer. To the mixture was added 20 mL ofconcentrated hydrochloric acid. The emulsion did not dissolve. Thephases were separated, and the aqueous phase was back-extracted with2×200 mL of MTBE. The combined organics were washed with 1×200 mL of amixture of 1:1 brine and 1 M aqueous NaOH. A small amount of gummyorange material separated at the solvent interface and was discarded.The remaining organic phase was washed with 200 mL brine and dried overNa₂SO₄. Excess solvent was removed in vacuo to obtain 21.96 g of a darkamber liquid. The liquid was diluted with 25 mL heptane and purified bychromatography on a 450 g Supelco VersaPak™ silica gel column (gradientelution from 0 to 33% ethyl acetate/heptane over 15 column volumes).Isolated 13.14 g, pale yellow liquid (68% yield).

2-cyclohexyl-1-fluoro-3,5-dimethoxybenzene

13.04 g of 1-(2-fluoro-4,6-dimethoxyphenyl)cyclohexanol was weighed intoa 500 mL round bottom flask fitted with a stir bar and septum cap. Tothe solids was added 250 mL of 9:1 EtOAc:HOAc. The solution was spargedwith nitrogen for 5 min and charged with 2.58 g of 10 wt % palladium oncarbon. A hydrogen atmosphere over the reaction mixture was establishedand maintained with a balloon. The reaction was stirred at 70° C. for 20h, after which LC-MS analysis indicated the reduction was complete. Thecatalyst was removed by filtration through a Whatman GF/B glass fiberfilter and the solids washed thoroughly with 200 mL EtOAc. The filtratewas poured into a separatory funnel and washed with 200 mL of 2.5 Maqueous sodium hydroxide, 200 mL of water, and 200 mL of brine, driedover Na₂SO₄, and concentrated by rotary evaporation to obtain a clear,colorless liquid (11.67 g). The liquid was diluted with heptane andpurified by chromatography to obtain 8.67 g of a clear colorless oil(71%).

4-cyclohexyl-5-fluorobenzene-1,3-diol (4,5CHFR)

8.51 g of 4-cyclohexyl-1,3-dimethoxy-5-fluorobenzene and 32.93 g oftetrabutylammonium iodide were weighed into an oven dried 500 mL 2-neckround bottom flask fitted with a stir bar, thermometer, nitrogen inlet,and septum. A nitrogen atmosphere was established and maintainedthroughout the reaction. To the flask was added 200 mL of anhydrousCH₂Cl₂. The mixture was cooled to −78° C. in a dry ice/acetone bath. Tothe rapidly stirred mixture was added 90 mL of a 1.0 M solution of borontrichloride in CH₂Cl₂ over 30 min using a syringe pump. The mixture wasstirred at −78° C. for 15 min, then stirred at −2° C. for 3 h. LC-MSanalysis at 2.5 h showed all the starting material had converted toproduct. The reaction was quenched by slow addition of 100 mL water andthe mixture was stirred at room temperature 15 min. At this point, 50 mLof methanol was added to dissolve the solids, and the mixture wasstirred at room temperature for 30 min. Organic solvents were removed byrotary evaporation at 50° C. The remaining aqueous mixture was dilutedwith 400 mL water and extracted with MTBE (3×150 mL). The combinedorganic layers were extracted with 3×150 mL of 1.0 M aqueous NaOH. Thecombined aqueous extracts were made acidic by adding 40 mL concentratedhydrochloric acid. The acidic solution was extracted with 3 portions of150 mL of MTBE. The combined extracts were washed with brine and driedover Na₂SO₄. Excess solvent was removed on a rotary evaporator. Theresidue was dissolved in 10% ethyl acetate/heptane and purified bychromatography on a 330 g Isco RediSep™ silica gel column (gradientelution from 10 to 50% ethyl acetate/heptane). The collected fractionswere concentrated and the resulting solids recrystallized from 30 mL ofhot 1:1 1,2-dichloroethane:heptane to obtain 3.31 g of colorlessorthorhombic crystals. After removal of the solvent from the filtrate,the residue was recrystallized from 12 mL of hot 1:11,2-dichloroethane:heptane to obtain a second crop of 2.76 g of smallwhite crystals. A third crop of 472 mg of small pink crystals (themother liquor is red) was obtained in a similar fashion. The first andsecond crops were identical by ‘H-NMR, LC-MS, and TLC and were combinedto give the product. White crystalline solid, 6.07 g. 81% yield. ¹H NMR(DMSO-d₆, 400 MHz) δ: 9.43 (d, J=1.4 Hz, 1H), 9.32 (d, J=0.5 Hz, 1H),6.99 (dd, J=2.3, 1.2 Hz, 1H), 5.91 (dd, J=13, 2.3 Hz, 1H), 2.85 (tt,J=12, 3.3 Hz, 1H), 1.62-1.83 (m, 5H), 1.47-1.57 (m, 2H), 1.10-1.33 (m,3H).

Example 3 2-Ethyl-1,5-dihydroxy-3-trifluoromethyl-benzene (4,5 ETFMR)

1-(2-Iodo-4,6-dimethoxy-phenyl)-ethanone

To a solution of acetyl chloride (3.12 g, 39 mmol) in dichloromethane(100 mL) was added AlCl₃ (6.34 g, 47 mmol) at 0° C. over 30 min.1-Iodo-3,5-dimethoxy-benzene (10.5 g, 39 mmol) was added to the mixture.The reaction mixture was stirred at room temperature for 1 h. Then icewater (60 mL) was added. The aqueous layer was extracted withdichloromethane (2×30 mL), dried over sodium sulfate and concentrated,and purified by column chromatography (eluted with petroleum ether/ethylacetate=20:1˜1:1), to give the title compound (6 g, 50%).

1-(2,4-Dimethoxy-6-trifluoromethyl-phenyl)-ethanone

A mixture of 1-(2-iodo-4,6-dimethoxy-phenyl)-ethanone (3.17 g, 10.1mmol), difluoro-fluorosulfonyl-acetic acid methyl ester (7.9 g, 41.1mmol) and CuI (3.8 g, 20 mmol) in NMP (50 mL) was heated at 120° C.under nitrogen overnight. The mixture was filtered and diluted withwater (200 mL), and extracted with ethyl acetate (3×50 mL). The organiclayers were washed with brine (50 mL), dried over sodium sulfate andconcentrated and purified with column chromatography (eluted withpetroleum ether: ethyl acetate=20:1˜10:1) to give the title compound(1.6 g, 64%).

2-Ethyl-1,5-dimethoxy-3-trifluoromethyl-benzene

Zinc (8.4 g, 0.13 mol) was added over 10 min to a solution of1-(2,4-Dimethoxy-6-trifluoromethyl-phenyl)-ethanone (1.6 g, 6.4 mmol) inethyl ether (20 mL) and concentrated hydrogen chloride (20 mL) at 0° C.The mixture was stirred at room temperature for 2 h. The mixture wasfiltered off, extracted with ethyl ether (3×50 mL), washed with brine(30 mL), dried over sodium sulfate and concentrated, and purified bycolumn chromatography (eluted with petroleum ether) to give the titlecompound (0.4 g, 27%).

2-Ethyl-1,5-dihydroxy-3-trifluoromethyl-benzene (4,5 ETFMR)

BBr₃ (12 mL, 0.67 mol/L) was added to a mixture of2-ethyl-1,5-dimethoxy-3-trifluoromethyl-benzene (0.4 g, 1.9 mmol) indichloromethane (10 mL), and the mixture was stirred at room temperaturefor 4 h. Methanol (5 mL) was added slowly to the mixture at 0° C., andthe mixture was concentrated to give an oil residue, which was dilutedwith water (20 mL), extracted with dichloromethane (4×10 mL), washedwith brine (10 mL), concentrated, and purified by pre-HPLC to give thetitle compound (140 mg, 40%). LC-MS 205 (M−1). ¹H NMR (400 MHz, CDCl₃)δ6.69 (d, J=2.0 Hz, 1H), 6.48 (d, J=2.0 Hz, 1H), 5.06 (s, 1H), 4.99 (s,1H), 2.70 (q, J=7.6 Hz, 2H), 1.16 (t, J=7.6 Hz, 3H). ¹⁹F NMR (400 MHz,CDCl₃) δ−60.2 (s).

Example 4 4-cyclohexyl-3-trifluoromethyl benzene-1,3-diol (4,5CHTFMR)

1-iodo-3,5-dimethoxy-benzene

A mixture of 1-bromo-3,5-dimethoxy-benzene (9.6 g, 44 mmol), CuI (0.7 g,3.6 mmol), NaI (13.3 g, 88 mmol) and MeNHCH₂CH₂NHMe (0.78 mL) in1,4-dioxane (80 mL) was degassed and filled with nitrogen in a sealedtube. The reaction mixture was heated at 120° C. for 20 h. The mixturewas cooled to room temperature. Water (100 mL) was added, and themixture was extracted with ethyl acetate (2×60 mL). The organic layerswere washed with brine (50 mL), dried over sodium sulfate, andconcentrated to give the title compound (10 g, 86%).

1,3-Dimethoxy-5-trifluoromethyl-benzene

A mixture of 1-iodo-3,5-dimethoxy-benzene (1.6 g, 6.0 mmol),difluoro-fluorosulfonyl-acetic acid methyl ester (3.1 mL, 24 mmol), andCuI (3.4 g, 18 mmol) in NMP (30 mL) was heated at 120° C. for 16 h, thenthe mixture was cooled to room temperature and water (50 mL) was added.The mixture was extracted with ethyl acetate (200 mL), washed with water(2×50 mL), and the organic layer was dried over sodium sulfate andconcentrated. The crude product was purified by column chromatography(eluted with petroleum ether) to give the title compound (0.54 g, 44%).

2-bromo-1,5-dimethoxy-3-trifluoromethyl-benzene

A mixture of NBS (2.75 g, 16.9 mmol) and1,3-dimethoxy-5-trifluoromethyl-benzene (3.5 g, 16.9 mmol) indichloromethane was stirred at room temperature for 16 h. The mixturewas concentrated and purified by column chromatography (eluted withpetroleum ether:ethyl acetate=5:1) to obtain the title compound (4 g,83%). ¹H NMR (400 MHz, CDCl₃) δ6.84 (d, J=2.8 Hz, 1H), 6.63 (d, J=2.8Hz, 1H), 3.91 (s, 3H), 3.84 (s, 3H). ¹⁹F NMR (360 MHz, CDCl₃) δ−62.7(s).

2-cyclohex-1-enyl-1,5-dimethoxy-3-trifluoromethyl-benzene

To a mixture of 2-bromo-1,5-dimethoxy-3-trifluoromethyl-benzene (50 mg,0.175 mmol), Pd(PPh₃)₂Cl₂ (12 mg, 0.0175 mmol), and K₂CO₃ (97 mg, 0.7mmol) in mixed solvents (DMF/MeOH, 3:1, 1.2 mL) in a sealed tube wasadded 2-cyclohex-1-enyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (73 mg,0.35 mmol). The tube was degassed and back-filled with N₂ (3×) andsealed under N₂. The tube was heated on oil bath to 100° C. for 6 h.After being cooled to room temperature, the reaction mixture was dilutedwith ethyl acetate/hexane and water. The organic layer was washed withbrine, dried with Na₂SO₄, concentrated, and purified by prep TLC (ethylacetate/hexanes, 8:2) to give the title compound (22 mg, 44%).

2-cyclohexyl-1,5-dimethoxy-3-trifluoromethyl-benzene

2-Cyclohex-1-enyl-1,5-dimethoxy-3-trifluoromethyl-benzene (800 mg, 2.8mmol) and MeOH (40 mL) were charged into a 200-mL round bottom flaskfitted with a stir bar and septum cap. The solution was sparged withnitrogen for 5 min. To the mixture 10 wt % palladium on carbon (400 mg)was added. The flask was vacuumed and filled with a hydrogen balloon.The reaction mixture was stirred at 50° C. for 16 h. The reactionmixture was filtered and concentrated to give a residue, which waspurified by silica gel column chromatography with ethyl acetate/hexanesto give the title compound (480 mg, 59%) as a white solid.

4-cyclohexyl-3-trifluoromethyl benzene-1,3-diol (4,5CHTFMR)

To a solution of 4-cyclopentyl-1,3-dimethoxy-5-methylbenzene (480 mg,1.67 mmol) in anhydrous CH₂Cl₂ (15 mL) at −78° in a dry ice/acetone bathwas added boron tribromide (1.25 g, 5.0 mmol). The reaction mixture wasstirred at −78° for 5 min and slowly warmed to room temperatureovernight. The reaction mixture was quenched by slow addition of water(50 mL). The mixture was extracted with ether (3×). The combined organicextracts were washed with brine, dried over Na₂SO₄, and concentrated togive a residue, which was purified by silica gel column chromatographywith ethyl acetate/hexanes to give the title compound (300 mg, 69%).LC-MS: 259 (M−1). ¹H NMR (400 MHz, CDCl₃) δ6.69 (d, 1H), 6.40 (d, 1H),5.11 (s, 1H), 5.07 (s, 1H), 2.88 (m, 1H), 1.99 (m, 2H), 1.69 (M, 4H),1.29 (M, 4H).

Example 5 4-hexyl-5-methylbenzene-1,3-diol (4,5HMR)

The title compound may be prepared using methods analogous to thosedescribed in the Examples and general synthetic schemes. LC-MS: 209.0(M+1). ¹H NMR (400 MHz, DMSO-d₆) δ8.87 (s, 1H), 8.79 (s, 2H), 6.07 (d,1H), 5.98 (d, 1H), 2.34 (s, 2H), 2.07 (s, 3H), 1.23 (m, 8H), 0.83 (t,3H).

Example 6 4-isopropyl-5-methylbenzene-1,3-diol (4,5IPMR)

The title compound may be prepared using methods analogous to thosedescribed in the Examples and general synthetic schemes. ¹H NMR (400MHz, DMSO-d₆) δ8.83 (s, 1H), 8.78 (s, 1H), 6.05 (d, 1H), 5.94 (d, 1H),3.04 (m, 1H), 2.09 (s, 3H), 1.20 (s, 3H), 1.18 (s, 3H).

Example 7 4-butyl-5-methylbenzene-1,3-diol (4,5BMR)

The title compound may be prepared using methods analogous to thosedescribed in the Examples and general synthetic schemes. LC-MS: 180.8(M+1). ¹H NMR (400 MHz, DMSO-d₆) δ8.87 (s, 1H), 8.78 (s, 1H), 6.07 (d,1H), 5.98 (d, 1H), 2.37 (t, 2H), 2.07 (s, 3H), 1.28 (m, 4H), 0.85 (t,3H).

Example 8 4-benzyl-5-methylbenzene-1,3-diol (4,5BnMR)

The title compound may be prepared using methods analogous to thosedescribed in the Examples and general synthetic schemes. ¹H NMR (400MHz, CDCl₃) δ7.27 (m, 2H), 7.17 (m, 3H), 6.30 (d, 1H), 6.22 (d, 1H),4.73 (s, 1H), 4.68 (s, 1H), 3.97 (s, 2H), 2.21 (s, 3H).

Example 9 4-cyclopropyl-5-methylbenzene-1,3-diol (4,5CPrMR)

The title compound may be prepared using methods analogous to thosedescribed in the Examples and general synthetic schemes. ¹H NMR (400MHz, DMSO-d₆) δ8.85 (s, 1H), 8.66 (s, 1H), 6.04 (d, 1H), 5.99 (d, 1H),2.17 (s, 3H), 1.35 (m, 1H), 0.75 (m, 2H), 0.45 (m, 2H).

Example 10 4-cyclopentylmethyl-5-methylbenzene-1,3-diol (4,5MCPMR)

The title compound may be prepared using methods analogous to thosedescribed in the Examples and general synthetic schemes. LC-MS: 207.0(M+1). ¹H NMR (400 MHz, DMSO-d₆) δ8.85 (s, 1H), 8.79 (s, 1H), 6.08 (s,1H), 5.99 (s, 1H), 2.39 (d, 2H), 2.08 (s, 3H), 1.99 (m, 1H), 1.52 (m,6H), 1.18 (m, 2H).

Example 11 4-cyclopentyl-5-methylbenzene-1,3-diol (4,5CPMR)

The title compound may be prepared using methods analogous to thosedescribed in the Examples and general synthetic schemes. LC-MS: 193.1(M+1). ¹H NMR (400 MHz, CDCl₃) δ6.23 (d, 1H), 6.13 (d, 1H), 4.63 (s,1H), 4.58 (s, 1H), 3.25 (m, 1H), 2.27 (s, 3H), 1.88 (m, 6H), 1.67 (m,2H).

Example 12 4-ethyl-5-methylbenzene-1,3-diol (4,5EMR)

The title compound may be prepared using methods analogous to thosedescribed in the Examples and general synthetic schemes. LC-MS: 152.8(M+1). ¹H NMR (400 MHz, DMSO-d₆) δ8.87 (s, 1H), 8.76 (s, 1H), 6.08 (s,1H), 5.99 (s, 1H), 2.38 (q, 2H), 2.08 (s, 3H), 0.93 (t, 3H).

Example 13 4-sec-butyl-5-methylbenzene-1,3-diol (4,5sBMR)

The title compound may be prepared using methods analogous to thosedescribed in the Examples and general synthetic schemes. LC-MS: 181.15(M+1). ¹H NMR (400 MHz, CD₃OD) δ6.21 (s, 1H), 6.11 (s, 1H), 4.80 (m,2H), 2.92 (m, 1H), 1.80 (m, 2H), 1.26 (d, 3H), 0.82 (t, 3H).

Example 14 4-(1-phenylethyl)-5-methylbenzene-1,3-diol (4,5PEMR)

The title compound may be prepared using methods analogous to thosedescribed in the Examples and general synthetic schemes, LC-MS: 229.0(M+1). ¹H NMR (400 MHz, CDCl₃) δ7.32 (m, 3H), 7.25 (m, 2H), 6.29 (d,1H), 6.13 (d, 1H), 4.64 (s, 1H), 4.50 (m, 2H), 2.32 (s, 3H), 1.63 (t,3H).

Example 15 4-(2,2,2-trifluoroethyl)-5-methylbenzene-1,3-diol (4,5TFEMR)

The title compound may be prepared using methods analogous to thosedescribed in the Examples and general synthetic schemes. ¹H NMR (400MHz, CD₃OD) δ6.16 (s, 2H), 3.43 (q, 2H), 2.20 (s, 3H).

Example 16 4-cyclohexyl-5-fluorobenzene-1,3-diol (4,5EFR)

The title compound may be prepared using methods analogous to thosedescribed in the Examples and general synthetic schemes. ¹H NMR(DMSO-d₆, 400 MHz) δ: 9.48 (s, 1H), 9.33 (s, 1H), 6.12 (dd, J=2.3, 1.3Hz, 1H), 5.96 (dd, J=12, 2.3 Hz, 1H), 2.85 (qd, J=7.4, 1.2 Hz, 2H), 1.01(t, J=7.4 Hz, 3H).

Example 17 2-Benzyl-1,5-dihydroxy-3-trifluoromethyl-benzene (4,5BNTFMR)

LC-MS: 267 (M−1). ¹H NMR (400 MHz, CDCl₃) δ7.14-7.28 (m, 5H), 6.81 (d,J=2.0 Hz, 1H), 6.52 (s, 1H), 5.11 (s, 1H), 4.98 (s, 1H), 4.11 (s, 2H).¹⁹F NMR (360 MHz, CDCl₃) δ−59.7 (s).

Example 18 Mushroom Tyrosinase Inhibition Assay

10 μM compound, 300 μM L-Tyrosine, and 84 units/mL of mushroomtyrosinase (Sigma T3824) were combined into 0.05 M potassiummonophosphate buffer at pH=6.5, and incubated for 15 min at roomtemperature. Absorbance was recorded at 490 nm. % tyrosinase inhibitionwas calculated as follows: (Abs_(DMSO)−Abs_(cmpd))/Abs_(DMSO)×100. Theassay was performed for various compounds described herein, as well asfor control compounds 4-ethyl resorcinol (4ER), 4-isopropylresorcinol(4IPR), 4-hexylresorcinol (4HR), 4-cyclohexylresorcinol (4CHR),5-methylresorcinol (5MR), kojic acid (KA), and hydroquinone (HQ),structures of which are shown below. Results are shown in Table 1.

TABLE 1 Mushroom Tyrosinase (% remaining enzyme activity) % TYR CompoundActivity 4,5CHMR 22 4,5 BMR 18 4,5BnMR 97 4,5TFEMR 103 4,5sBMR 1004,5HMR 10 4,5CPMR 71 4,5CPrMR 30 4,5PEMR 105 4,5EMR 93 4,5IPMR 1084,5MCPMR 32 4,5ETFMR 102 4,5CHTFMR 100 4,5BnTFMR 93 4,5EFR 3 4,5CHFR 14ER 2 4IPR 1 4HR 1 4CHR 0 5MR 100 Hydroquinone 100 Kojic Acid 84

Example 19 Mammalian Tyrosinase Inhibition Assay

B16F1 cells are grown in Dulbecco's Modified Eagle Medium (DMEM) 10%FBS, P/S at 10% CO₂ and 37° C. to 90% confluency. Cell lysate isprepared with 150 mM NaCl; 20 mM Tris-HCl, pH=7.4; and 1% Triton-X100.The assay is conducted in buffer (0.05M potassium monophosphate buffer,pH=6.5, 600 uM L-Tyrosine, 15 uM L-Dopa, 0.325 mg/mL B16F1 cell lysate)with 10 μM compound. After mixing, the reaction mixture is incubated at37° C. for 8 h and absorbance measured at 490 nm. % tyrosinaseinhibition is calculated as follows:(Abs_(DMSO)−Abs_(cmpd))/Abs_(DMSO)×100.

Example 20 B16 Melanin Assay

B16F1 cells were grown in phenol free DMEM 10% FBS, P/S at 10% CO₂ and37° C. After trypsinization, cells were seeded at 3,000 cells per wellin a 96-well plate and allowed to attach overnight. 1 mM Theophyllinewas used to stimulate melanogenesis, and the compound of interest wasadded. After 72 h growth at 10% CO₂ and 37° C., media absorbance wasmeasured at 405 nm and corrected for cellular viability measured withCalcein-AM. % melanin content was calculated as follows:(Abs_(DMSO)/Calcein_(DMSO)−Abs_(cmpd)/Calcein_(cmpd))/Abs_(DMSO)/Calcein_(DMSO)×100.The assay was performed for various compounds described herein, as wellas for control compounds 4ER, 4IPR, 4HR, 4CHR, 5MR kojic acid, andhydroquinone. Results are shown in Table 2.

TABLE 2 B16 Media Melanin (% Melanin) % Melanin Compound B16 4,5CHMR 584,5 BMR 55 4,5BnMR 86 4,5TFEMR 90 4,5sBMR 76 4,5HMR 78 4,5CPMR 614,5CPrMR 62 4,5PEMR 87 4,5EMR 69 4,5IPMR 71 4,5MCPMR 90 4,5ETFMR 684,5CHTFMR 65 4,5BnTFMR 82 4,5EFR 87 4,5CHFR 51 4ER 48 4IPR 77 4HR 714CHR 63 5MR 100 Hydroquinone 100 Kojic Acid 100

Example 21 Melanocyte-HaCaT Co-Culture Assay

Darkly pigmented human neonatal epidermal melanocytes (HEMn-DP,Invitrogen) were grown in Medium 254 with HMGS-2 supplement and P/S at37° C. and 5% CO₂. HaCaT cells were grown in DMEM, 10% FBS, P/S at 37°C., 5% CO₂. Co-culture was conducted in 50% melanocyte media+50%keratinocyte media (EpiLife with EDGS, P/S). Cells were plated in theco-culture media at 40K (HaCaT) and 30K (HEMn-DP) per well in a 24-wellplate. After 24 h of incubation at 37° C. and 5% CO₂, media was changedto M153 (MCDB153 Sigma M7403 with NaHCO₃ pH to 7.1, 2 mM Tyrosine, 10 nMNDP-aMSH, 3 ng/mL bFGF, 2.8 ug/mL Hydrocortisone, 10 ug/mL Insulin, 10ug/mL Transferrin, and P/S), treated with compound, and incubated for 72h at 37° C. and 5% CO₂. After measuring cellular viability withCalcein-AM (RFU Ex/Em=488/525 nm), cells were lysed at 1 h at 65° C.with 1N NaOH+10% DMSO. Absorbance of cleared lysate was measured at 405nm and 660 nm. % melanin was calculated as follows:((Abs405_(DMSO)−Abs660_(DMSO))/Calcein_(DMSO))−(Abs405_(comp)−Abs660_(comp))/Calcein_(comp)))/(Abs405_(DMSO)−Abs660_(DMSO))/Calcein_(DMSO)×100.At 10 μM concentration, % cellular melanin was 42% in the presence ofcompound 4,5CHMR.

Example 22 Mattek 3D Skin Equivalents

MelanoDerm (Mel-300-B) assay was conducted according to themanufacturer's instruction (MatTek Corporation). Every other day, thetest articles were administered into the EPI-100-NMM-113 culture medium,and positive control, 25 uL of 2% Kojic acid was applied topically.After 14 days, tissue viability and melanocyte morphology were visuallyverified and tissue melanin was extracted and quantitated against astandard curve. % melanin was calculated as follows:(Melanin_(DMSO)−Melanin_(comp))/Melanin_(DMSO)×100. The assay wasperformed for various compounds described herein, as well as for controlcompounds 4ER, 4IPR, 4HR, 4CHR, kojic acid, and hydroquinone. Resultsare shown in Table 3.

TABLE 3 MatTek Assay (% Melanin) % Melanin 3D EpiDerm Compound 30 μM 10μM 4,5CHMR 44 66 4,5 BMR 64 81 4,5BnMR 61 82 4,5TFEMR 72 81 4,5sBMR 6775 4,5HMR 68 77 4,5CPMR 55 65 4,5CPrMR 82 99 4,5PEMR 62 98 4,5EMR 79 1024,5IPMR 72 102 4,5MCPMR 72 94 4,5ETFMR 66 81 4,5CHTFMR 89 4,5BnTFMR 7593 4,5CHFR 81 87 4ER 61 84 4IPR 46 71 4HR 72 93 4CHR 36 65 Hydroquinone92 94 Kojic Acid 100 100 KA topical 75

Example 23 Clinical Evaluation for Dark Circles

Female subjects with mild to moderate dark circles under their edges arerecruited for the study after providing informed consent. The study isconducted in accordance with all applicable government regulations andinstitutional policies. Both an expert grader and the subjects evaluatethe severity of the dark circles under their eyes prior to applicationof test products. A composition containing one or more compounds asdescribed herein is topically applied to the skin area around one eyeand a composition not containing the compounds described herein aroundthe opposite eye as a control. Treatment assignments are randomizedacross the panel, and neither the subject nor the grader has knowledgeof the treatment code. One hour after product application, both thegrader and subject separately evaluate the appearance of the darkcircles under the eyes.

Example 24 Clinical Evaluation for Puffiness

A set of female subjects with puffiness under their eyes is recruitedafter providing informed consent. The study is conducted in accordancewith all applicable government regulations and institutional policies. Acomposition containing a compound described herein is applied under oneeye, and a composition with no compound as described herein is appliedunder the other eye as a control. The subjects use the product for 4weeks, returning at week 2 for another dermatological evaluation. After2 and 4 weeks of product use, both the subjects and the dermatologistevaluate the improvement in the puffiness of the eyes compared with thebaseline observations.

Example 25 Clinical Evaluation for Aging Signs

A set of male and female subjects is recruited after providing informedconsent. The study is conducted in accordance with all applicablegovernment regulations and institutional policies. Expert graderstrained in visual and tactile evaluations assess the different agingsigns of the face of each subject by grading on a semi-structured scale.Each subject is characterized by a quantitative profile of his or heraging signs and two expert graders evaluate each parameter at each timepoint. A composition containing a compound described herein is appliedto one section of the face, and a composition with no compound asdescribed herein is applied to another section of the face as a control.The subjects use the product for 4 weeks, returning at week 2 and week 4for an evaluation by the graders.

Mean values and standard deviation are calculated, as well as variationsof the parameter relative to before application (expressed inpercentage). A Paired Student's t test is used to determine thesignificance of the results.

While the present compositions and methods have been described withreference to the specific variations thereof, it should be understood bythose skilled in the art that various changes may be made andequivalents may be substituted without departing from the true spiritand scope of the compositions and methods described herein. In addition,many modifications may be made to adapt a particular situation,material, composition of matter, process, process step or steps, to theobjective, spirit and scope of the compounds and methods describedherein. All patents and publications cited above are hereby incorporatedby reference.

1. A cosmetic or dermatological composition comprising one or more resorcinols of formula I:

wherein R¹ and R² are independently alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —F, or —Cl, each of which alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with —OH, —OR³, —NR³R⁴, —C(O)OR³, —C(O)NR³R⁴, or halo; and R³ and R⁴ are independently hydrogen, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, aryl, or heteroaryl; or a pharmaceutically acceptable salt thereof.
 2. The composition of claim 1, comprising a compound of formula I wherein R¹ is alkyl, perhaloalkyl, —F, or —Cl; and R² is alkyl or cycloalkyl.
 3. The composition of claim 1, comprising a compound of formula I wherein R¹ is alkyl.
 4. The composition of claim 3, comprising a compound of formula I wherein R¹ is methyl.
 5. The composition of claim 1, comprising a compound of formula I wherein R¹ is trifluoromethyl.
 6. The composition of claim 1, comprising a compound of formula I wherein R¹ is fluoro.
 7. The composition of claim 1, comprising a compound of formula I wherein R¹ is chloro.
 8. The composition of claim 1, comprising a compound of formula I wherein R² is alkyl.
 9. The composition of claim 8, comprising a compound of formula I wherein R² is ethyl.
 10. The composition of claim 8, comprising a compound of formula I wherein R² is hexyl.
 11. The composition of claim 1, comprising a compound of formula I wherein R² is cycloalkyl.
 12. The composition of claim 11, comprising a compound of formula I wherein R² is cyclohexyl.
 13. The composition of claim 1, comprising a compound of formula I wherein the compound is

or a pharmaceutically acceptable salt thereof.
 14. A cosmetic or dermatological composition comprising a therapeutically effective amount of the composition of claim 1 and a pharmaceutically, dermatologically, or cosmetically acceptable carrier.
 15. A method of regulating or preventing a skin condition wherein the skin condition is characterized by oxidative stress or a degenerative process, comprising administering to a subject exhibiting said skin condition an effective amount of the composition of claim
 1. 16. A method of reducing or treating the signs of skin aging or of reducing the appearance of signs of skin aging comprising administering to a subject exhibiting said skin condition an effective amount of the composition of claim
 1. 17. A method of regulating or preventing a skin condition associated with visible discontinuities of the skin, comprising administering to a subject exhibiting said skin condition an effective amount of the composition of claim
 1. 18. The method of claim 17, wherein the visible discontinuities are associated with aging, age-related damage or damage resulting from extrinsic factors.
 19. The method of claim 17, wherein the visible discontinuities of the skin are associated with pigmentation disorders.
 20. The method of claim 19, wherein the pigmentation disorders are selected from a group consisting of uneven pigmentation, age spots, vitiligo and melasma.
 21. A method for preventing, lightening or reducing the appearance of visible discontinuities of the skin, comprising administering to a subject exhibiting said skin conditions an effective amount of the composition of claim
 1. 22. A method of regulating or preventing a skin condition wherein the skin condition is associated with visible discontinuities of the skin, while concurrently reducing or treating the signs of skin aging, comprising administering to a subject exhibiting said skin condition an effective amount of the composition of claim
 1. 23. The method of claim 22, wherein the visible discontinuities of the skin are selected from uneven pigmentation, age spots, vitiligo and melasma.
 24. The method of claim 22, wherein the visible discontinuities of the skin are a result of harmful ultraviolet radiation, pollution or other environmental insults, stress, or fatigue.
 25. A method of preventing, lightening, or reducing the appearance of visible discontinuities of the skin, while concurrently reducing or treating the signs of skin aging, comprising administering to a subject exhibiting said skin condition an effective amount of the composition of claim
 1. 26. The method of claim 25, wherein the visible discontinuities of the skin are selected from a group consisting of uneven pigmentation, age spots, vitiligo and melasma.
 27. The method of claim 26, wherein the visible discontinuities of the skin are a result of harmful ultraviolet radiation, pollution or other environmental insults, stress, or fatigue.
 28. (canceled) 